Substituted piperidines

ABSTRACT

The compounds are of the heterocyclic class of 2-phenethylpiperidines having an amido substituent in the ortho position of the phenethyl moiety. Substituents in the ortho position include formamido, benzamido, cinnamamido, 2-thiophenecarboxamido, alkanesulfonamido and alkanoylamido. They are useful as antiarrhythmic and/or antiserotonin agents. The novel compounds are prepared by reaction of appropriately substituted o-aminophenethylpiperidines and the carbonyl or sulfonyl halides or anhydrides. Typical embodiments of this invention are 4-methoxy-2&#39;-[2-(1-methyl-2-piperidyl)ethyl]benzanilide and 2&#39;-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending U.S. application Ser. No.384,341 filed July 31, 1973 now U.S. Pat. No. 3,931,195 granted Jan. 6,1976, which is a continuation-in-part of then co-pending U.S.application Ser. No. 120,754 filed Mar. 3, 1971, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with certain heterocyclic organiccompounds which can be referred to as substituted piperidines and acidaddition salts thereof. In particular, this invention relates tophysiologically active novel piperidine compounds which are particularlyeffective as antiarrhythmic and antiserotonin agents. It is alsoconcerned with chemical intermediates useful in the preparation of thepiperidine compounds. Other features of the invention are pharmaceuticalcompositions containing the piperidines as active ingredients and atherapeutic process for producing antiserotonin and antiarrhythmiceffects in mammals by administration of them.

Agents which antagonize serotonin are of interest in experimentalbiology and in treatment of various physiological disorders such asmigraine headache, serotonin producing tumors, toxemia in pregnancy,habitual abortion and management of various inflammatory and allergicreactions. Methysergide and lysergide are well known antiserotoninagents. Other serotonin antagonists which have been reported in theprior art literature on the subject are2'-(3-dimethylaminopropylthio)cinnamanilide and related compoundsdisclosed by Krapcho, et al., J. Med. Chem., 6, 219 (1963); 7, 376(1964); 9, 809 (1966); and 12, 164 (1969); and U.S. Pat. No. 3,192,213.

A number of structurally unrelated chemical substances have beenemployed in the treatment of cardiac arrhythmia; refer to A. Burger,Medicinal Chemistry, 3rd Edition, pages 1082-1085 (Wiley). One of themost important drugs in clinical treatment of disorders of cardiacrhythm is quinidine. Another chemical agent which has been used as anantiarrhythmic is the local anesthetic procaine amide. Still otherantiarrhythmic agents are lidocaine, and diphenylhydantoin. None ofthese compounds are structurally related to the piperidines of thepresent invention.

SUMMARY OF THE INVENTION

This invention relates to a series of substituted piperidinescharacterized by Formula I and Formula XII and non-toxicpharmaceutically acceptable acid addition salts thereof. ##STR1##

The substances of Formula I and Formula XII are new compositions ofmatter possessing valuable pharmacological properties which render themuseful as synthetic medicinals. In particular, the substitutedpiperidines of Formula I and Formula XII exhibit utility asantiserotonin and/or antiarrhythmic agents in standard pharmacologicaltests in mammals. This invention also is concerned with the productionof the compounds of Formulas I and XII from novel chemicalintermediates, pharmaceutical compositions containing them and atherapeutic process for producing an antiserotonin effect in mammalscomprising the administration of such compounds thereto. Another featureof this invention is a therapeutic process for producing anantiarrhythmic effect in mammals by administration of compounds ofFormula I wherein R⁵ is R⁶ substituted cinnamoyl as depicted by FormulaIa or R⁷ substituted benzoyl as depicted by Formula Ib.

Still another feature of this invention provides novelo-amino-phenethylpiperidines of Formula II which are useful as chemicalintermediates in the production of compounds of Formula I. ##STR2##

In the compounds characterized by the above general Formulas I and II,the R¹ substituent stands for hydrogen or lower alkyl. The substituentR² represents hydrogen, lower alkoxy or methylenedioxy attached in thebenzenoid 4,5-position. R³ stands for hydrogen or a lower alkylsubstituent. Substituent R⁴ represents hydrogen, lower alkyl, or adialkylcarboxamido substituent wherein the dialkyl groups are loweralkyl.

Substituent R⁵ represents radicals selected from the group comprised oflower alkanoyl of from 1 to 4 carbon atoms inclusive, loweralkanesulfonyl of from 1 to 4 carbon atoms inclusive, ##STR3##

The symbol R⁶ represents hydrogen or lower alkyl and R⁷ is selected fromthe group consisting of hydrogen, halogen, trifluoromethyl, amino,dimethylamino, hydroxy, acetoxy, carboxy, alkylthio of from 1 to 4carbon atoms inclusive, alkyl of from 1 to 4 carbon atoms inclusive,lower alkoxy of from 1 to 4 carbon atoms inclusive, and wherein when R⁷is hydrogen or alkoxy the phenyl ring can have up to 2 additional alkoxysubstituents of from 1 to 4 carbon atoms inclusive.

In the compounds characterized by Formula XII, the symbol R⁸ representshydrogen or lower alkyl. The symbol R⁹ represents a radical selectedfrom the group consisting of cinnamoyl or ##STR4## wherein R¹⁰ is loweralkoxy. The symbol A represents a divalent radical selected from thegroup consisting of

It is to be understood that the term "lower alkyl" and "lower alkoxy" asused herein refers to carbon chains which include both straight andbranched chain carbon radicals of from 1 to 4 carbon atoms inclusive.Illustrative of these radicals are carbon chains which can be methyl,ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl andtert.-butyl.

Compounds which are particularly preferred for their strongantiserotonin activity are compounds of Formula Ia. ##STR5## wherein R¹,R², R³, R⁴ and R⁶ have the meanings hereinabove given for Formula I.Representative of these compounds is the individually preferred compound2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide.

Compounds of the present invention which are particularly preferred fortheir strong antiarrhythmic activity are those of Formula Ib. ##STR6##wherein R¹, R², R³, R⁴, and R⁷ have the meanings hereinabove given forFormula I. Representative of these compounds are the individuallypreferred compounds4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, and2'-[2-(1-methyl-2-piperidyl)ethyl]-3,4,5-trimethoxybenzanilide.

A still further group of preferred compounds are those characterized byFormula Ib wherein R¹, R², and R⁴ are hydrogen, R³ is methyl and R⁷ ishydrogen or alkoxy.

A particularly preferred antiarrhythmic compound of Formula XII is2'-[3-(1-methyl-2-piperidyl)propyl]-p-anisanilide.

The o-aminophenethylpiperidines of Formula II are considered to beanother aspect of the present invention. They are particularly useful aschemical intermediates in the preparation of compounds of Formula I.Apart from being particularly suitable as key intermediates in thepreparation of compounds of Formula I, some of the members such as2-(o-aminophenethyl)-1-methylpiperidine have antiarrhythmic properties.

A compound of Formula XII particularly preferred as an antiarrhytmicagent is 2-2-[(p-methoxybenzyl)amino]phenethyl]-1-methylpiperidine andnon-toxic pharmaceutically acceptable salts thereof.

It will be apparent to those skilled in the art that the compounds ofFormula I, Formula II and Formula XII exists in at least one racemicstereoisomeric form since they contain one asymmetric carbon atom (the 2position of the piperidine ring). Whenever the R⁴ substituent is nothydrogen, an additonal asymmetric carbon atoms (the 5position of thepiperidine ring) is present and two racemic modifications exist. Suchmixture of racemates can be separated into the individual racemiccompounds on the basis of physico-chemical differences such assolubility; for example, by fractional crystallization of the basis oras acid addition salts thereof or by chromatography. Optically activestereoisomers are obtained by resolution methods well known to the artsuch as the use of optically active acids.

It is to be understood that as used herein, the term "non-toxicpharmaceutically acceptable acid addition salts" refers to a combinationof compounds of the present invention with relatively non-toxicinorganic or organic acids. Illustrative of suitable acids which may beused are sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic,sulfamic, methanesulfonic, benzenesulfonic, para-toluenesulfonic,acetic, lactic, succinic, maleic, mucic, tartaric, citric, gluconic,benzonic, cinnamic, isethionic and related acids.

The compounds characterized by Formula I and Formula XII exhibitvaluable antiarrhythmic activity in mammals. These antiarrhytmic effectsare illustratively demonstrated in standard in vitro and in vivopharmacological tests.

In the dog, for example, electrically or aconitine induced arrhythmia isprevented by oral or parenteral administration of the piperidines ofFormula I according to the following in vivo test.

The chest of an anesthetized dog is opened in the midline and the rightand left atrial appendages exposed through small slits in thepericardium. Bypolar recording electrodes are affixed to the atrialsurfaces and a 4 × 4 mm. piece of clean cloth is fixed to the surface ofthe right auricular appendage. Control recordings are made of variousheart functions including femoral arterial blood pressure and right andleft atrial electrograms. Atrial arrhythmia is then induced by placing3-5 drops of a solution of aconitine on the cloth which is fixed to theright atrium. An irregular, rapid atrial rate is produced within oneminute. Throughout the experiment, fresh aconitine is (2-3 drops) placedon the cloth at 10 minute intervals. The test compound is administeredintravenously five minutes after the initial establishment of thearrhythmia and infusion continued at a slow rate until an effective dosewhich re-establishes normal rhythm of the heart is obtained. Intravenousadministration of as little as 0.8 mg./kg. of4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, a preferredcompound of the present invention, effectively restores normal cardiacrhythm to aconitine induced arrhythmia in the dog. A well knownantiarrhythmia agent such as quinidine administered in the same mannerhas an effective dose of 6.0 mg./kg. When arrhythmia is inducedelectrically, the effective dose of4-methoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide is 1.9 mg./kg.Under like conditions, the effective dose for quinidine is 14 mg./kg.

Intraduodenal administration, which is a measure of oral effectiveness,of 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide preventsaconitine induced arrhythmia in the dog at a dose of less than 10mg./kg. while the effective dose in the prevention of aconitine inducedarrhythmia for quinidine is greater than 14 mg./kg.

Another in vivo test involves the inhibition of chloroform inducedarrhythmia in the mouse according to the method of J. W. Lawson, J.Pharmacol. Exp. Therap., 160, 22 (1968). Intraperitoneal administrationof 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide to the mouseprevents chloroform induced arrhythmia at an ED₅₀ of 7.1 mg./kg.compared to an ED₅₀ of 83 for quinidine.

An in vitro test which demonstrates the antiarrhythmic effects of thecompounds of the present invention employs the rabbit atrium. In thistest, the left atrium is placed in Chenoweth's solution warmed to 30° C.and irrigated with 95% oxygen: 5% carbon dioxide. The lower end of theatrium is attached to a small hook fixed in the bath and the upper endis connected to a transducer to record contractile activity. The atriumis electrically stimulated at a basic rate of 30 per minute employingsquare wave pulses of 10 millisecond duraction at 1.2-1.5 × thresholdvoltage. A test compound is introduced into the bath and the testrepeated after a 5 minute interval. A dose-response relationship isobtained by additional doses of the test compound. The potency of a testagent can be expressed as the effective concentration which produces 50%of the maximal increase in the measured refractory period of the steadystate atrium. This value is designated the EC₅₀.

In the in vitro rabbit atrium test, the ED₅₀ of4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide is 2.4 microgramper milliliter while the value for quinidine is 18.0 microgram permilliliter.

Exemplary of compounds of the present invention which have particularlygood antiarrhythmic properties are:

2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide,

4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide,

4-chloro-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide,4-amino-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide,

4-acetoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]-3,4,5-trimethoxybenzanilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]-2-thiophenecarboxanilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]methanesulfonanilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide,

2-(o-aminophenethyl)-1-methylpiperidine,

2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide,

2'-[3-(1-methyl-2-piperidyl)propyl]-p-anisanilide.

The compounds of Formula Ia and Formula Ib are characterized asparticularly useful antiserotonin agents as can be demonstrated in therat uterus. According to this test one of the uterine horns of a ratuterus is suspended in oxygenated salt solution at 30° C. Thecontractions of this tissue are then recorded and varying concentrationsof the test compound introduced into the bath in order to determine theconcentration that would decrease the spasmogenic effect of 0.4microgram per milliliter of serotonin by 50%. This value is designatedthe IC₅₀.

A preferred antiserotonin compound of the present invention is2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, which has an IC₅₀ of0.00185 microgram per milliliter. Another preferred substance,4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, has an IC₅₀ of0.0046 microgram per milliliter. The antiserotonin agents lysergide(LSD) and methysergide have an IC₅₀ of 0.012 and 0.0025 microgram permilliliter respectively.

The antiarrhythmic and antiserotonin therapeutic process of the presentinvention is carried out in mammals by systemic administration of anon-toxic effective dose of the piperidines of Formulas I and XIIranging from about 0.01 to 20 milligram per kilogram of body weight ofthe mammal or more preferably from 0.1 to 10 mg./kg. Acceptable forms ofsystemic administration are oral and parenteral. Examples of parenteraladministration are intramuscular, intravenous, intraperitoneal, andsubcutaneous administration. The dosage of the present therapeuticagents of Formulas I and XII will vary with the form of administrationand particular compound chosen. Generally, the compound is administeredat a dosage substantially less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. It will generally befound that when the composition is administered orally, largerquantities of the active agent will be required to produce the sameeffect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

The antiserotonin activity of2'-[2-(1-methyl-2-piperidyl)ethyl]-cinnamanilide can also bedemonstrated in mice according to the method of S.J. Corne, et al.,Brit. J. Pharmacol., 20, 106 (1963). This test is dependent on themetabolism of 5-hydroxytryptophan to serotonin in the brain in micewhich are pretreated with a monamine oxidase inhibitor. Depending on theroute of administration and the pretreatment time, the following ED₅₀values are obtained: subcutaneous, 4.3 mg./kg. (30 minute pretreatment),10 mg./kg. (60 minute pretreatment); intraperitoneal, 21 mg./kg. (60minute pretreatment). These values compare favorably with that obtainedwith methyldopa, a known serotonin inhibitor, which has anintraperitoneal ED₅₀ of 37 mg./kg. (60 minute pretreatment).

When the compounds of this invention characterized by Formulas I and XIIare employed as antiserotonin or antiarrhythmic agents they may beadministered to mammals alone or in combination with a pharmaceuticallyacceptable carrier. The proportion of the pharmaceutical carrier isdetermined by the solubility and chemical nature of the compound andchosen route of administration in standard pharmaceutical practice. Forexample, they may be administered orally in form of tablets, coatedtablets or capsules containing such excipients as starch, milk, sugar,certain types of clay, gelatin, stearic acid or salts thereof, magnesiumor calcium stearate, talc, vegetable fats or oils, gums, glycols, andother known excipients. They may be administered orally in the form ofsolutions which may contain coloring and flavoring agents or they may beinjected parenterally, that is intramuscularly, intravenously, orsubcutaneously. For parenteral administration they may be used in theform of sterile solution. Said pharmaceutical compositions are preparedby conventional methods.

A recommended dosage unit form comprises a pharmaceutical carrier andthe therapeutically active compound in an amount sufficient to provide anon-toxic effective antiserotonin or antiarrhythmic dose ranging fromabout 0.01 to 20 milligram per kilogram of body weight of the mammaltreated.

Advantageously, the compositions can be adapted to supply a fixed dosecontaining from 1 to 500 mg. and preferably 5 to 100 mg. of the activeingredient.

Preparation of compounds of Formula I according to the process of thepresent invention is carried out according to Equation 1. ##STR7##wherein R¹, R², R⁴, and R⁵ have the meaning stated above and R³ islimited to lower alkyl provided that when R⁵ is "R⁷ -benzoyl," R⁷additionally represents "NO₂ " but cannot stand for NH₂ or OH. Compoundswherein R⁷ is "NO₂ " are converted to compounds of Formula I wherein R⁷is "NH₂ " by hydrogenation. Compounds wherein R⁷ is "acetoxy" areconverted to compounds of Formula I wherein R⁷ is "OH" by hydrolysis.The symbol X represents a halogenide of a R⁵ carbonyl or sulfonylradical or R⁵ X taken together represents an anhydride.

Illustrative of R⁵ X reactants which can be reacted witho-aminophenethylpiperidines of Formula II are:

acetic-formic anhydride,

acetic anhydride,

n-propionic anhydride,

n-butyric anhydride,

isobutyric anhydride,

benzoic anhydride,

acetyl chloride,

propionyl chloride,

butyryl chloride,

methanesulfonyl chloride,

methanesulfonic anhydride,

ethanesulfonic anhydride,

isopropylsulfonyl chloride,

n-butanesulfonyl chloride,

4-methoxybenzoyl chloride,

3,4,5-trimethoxybenzoyl chloride,

3,5-dimethoxybenzoyl chloride,

2-methoxybenzoyl chloride,

2-chlorobenzoyl chloride,

3-acetoxybenzoyl chloride.

In addition R⁵ X taken together can represent a reactive ester such as,for example, methyl 4-(t-butoxy)benzoate, ethyl picolinate, ethylpropiolate, ethyl 4-dimethylaminobenzoate, ethyl furan-3-carboxylate andthe like.

The reaction proceeds when the reactants are contacted and mixed in aninert organic solvent as a reaction medium. Representative inert organicsolvents which can be employed as reaction media include ether, benzene,toluene, acetonitrile halogenated hydrocarbons such as chloroform, andthe like. Whenever halogenide reactants such as acetyl chloride, etc.,are employed, it is desirable to add a hydrogen halide acceptor such astriethylamine to the reaction mixture. Pyridine is preferredparticularly as a reaction medium because of its suitability both as asolvent and as an acid acceptor. The temperature at which the reactionis carried out is not critical, although from a convenience and ease ofoperability viewpoint, room temperature is preferred. The exactproportions of the reactants to be employed is not critical. However,since the o-aminophenethylpiperidines of Formula II and the R⁵ Xreactants are consumed in equimolar proportions, the reactants arepreferably employed in such proportions. The reaction is generallycomplete in about 1 to 24 hr. depending upon the reaction temperatureemployed. The product can be conveniently separated from the reactionmixture by concentrating the reaction mixture under reduced pressure,dissolving the resulting residue in water and adding thereto a base suchaqueous sodium hydroxide, aqueous sodium carbonate, or aqueous potassiumcarbonate to make the mixture strongly basic. The product can then beseparated by extraction with a halogenated hydrocarbon solvent, ether,benzene, ethyl acetate, etc. Generally, the product can be purified byrecrystallization from organic solvents such as isopropyl ether,heptane, methanol, ethanol, isopropyl alcohol, ethyl acetate, water,acetone, and the like, or it can be converted to an acid addition salt.Other means of purification include chromatography, e.g. thin-layer orcolumn.

Conversion of the substances characterized by Formula I and Formula XIIto pharmaceutically acceptable acid addition salts is accomplished byadmixture of the Formula I and Formula XII bases with substantially onechemical equivalent of any of the various acids hereinbefore defined.Generally the reactions are carried out in an inert solvent. Suitablesolvents by way of example, are ethanol, benzene, ethyl acetate, ether,and halogenated hydrocarbons.

Synthesis of the novel o-aminophenethylpiperidine intermediates ofFormula II begins with preparation of 2-styrylpyridines of Formula IIIwhich are obtained according to the method of L. Horwitz, J. Org. Chem.,21, 1039 (1956) from the reaction of a R² -o-nitrobenzaldehyde and a R⁴-2-methylpyridine. As shown in Equation 2, the nitro-2-styrylpyridinesof Formula III are reduced to an o-aminophenethylpyridine of Formula IV.It is preferred that reduction be carried out catalytically in a solventemploying palladium on carbon catalsyt. Suitable solvents by way ofexample are the lower alkanoyls such as methanol, ethanol, isopropanol,etc. ##STR8##

The o-aminophenethylpyridines of Formula IV are then formylated in orderto block alkylation of the aromatic amine when the R³ substituent isintroduced by quaternization of the pyridine nitrogen with an R³-halide. This conversion of the o-aminophenethylpyridines of Formula IVto the Formula V formyl derivative is illustrated by Equation 3 and ispreferably carried out with acetic-formic anhydride. ##STR9##

Equation 4 illustrates the alkylation of a Formula V pyridine with analkyl iodide to provide a pyridinium salt of Formula VI. Depending onthe R³ substituent desired, alkyl halides such as ethyl iodide, ethylbromide, n-propyl iodide, 2-iodopropane, 1-iodobutane,1-iodo-2-methylpropane, 1-chloro-2-methylpropane, 2-iodo-2-methylpropaneand the like are employed. The alkylation is carried out in an inertsolvent such as acetone, acetonitrile, etc. ##STR10##

Compounds of Formula VI are converted to the phenethylpiperidines ofFormula VII by reduction according to Equation 5. The reduction iscarried out catalytically employing platinum as the catalyst in asuitable solvent such as the lower alkanols. The phenethylpiperidines ofFormula VII can also be obtained by reduction first with metalborohydrides such as sodium borohydride, or potassium borohydride toprovide a tetrahydropyridine which is then further reduced by well knowncatalytic methods to the piperidines of Formula VII. For example,reduction of5-diethylcarbamyl-2-(o-formamidophenethyl)-1-methylpyridinium iodidewith sodium borohydride in methanol solution providesN,N-diethyl-6-(o-formamidophenethyl)-1-methyltetrahydropyridin-3-carboxamidewhich is then hydrogenated in ethanol with a 10% palladium on carboncatalyst. It will be recognized that compounds of Formula VII representthe products of Formula I of the present invention wherein R¹ ishydrogen and R⁵ is formyl. ##STR11##

Representative of the formanilides of Formula VII are:

2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide,

2'-[2-(5-methyl-1-methyl-2-piperidyl)ethyl]formanilide,

2'-[2-(5-n-butyl-1-methyl-2-piperidyl)ethyl]-formanilide,

2'-[2-(1-isopropyl-2-piperidyl)ethyl]formanilide,

2'-[2-(1-n-butyl-2-piperidyl)ethyl]formanilide,

4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formanilide,

4'-n-butoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formanilide,

4'-isopropoxy-2'-[2-(5-isopropyl-1-methyl-2-piperidyl)-ethyl]formanilide,

N,n-dimethyl-6-(o-formanidophenethyl)-1-methylpiperidine-3-carboxamide,

N,n-diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide

N,n-di-n-butyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide,

N,n-diethyl-6-(2-formamido-5-methoxyphenethyl)]-1-methylpiperidine-3.

If the o-aminophenethylpyridines of Formula IV are acylated withalkanoyl halides such as acetyl chloride, propionyl chloride, isobutyrylchloride, butyryl chloride and the like, and the sequence of reactionsillustrated by Equations 3-5 repeated, products of Formula I areobtained wherein R¹ is hydrogen and R⁵ is alkanoyl. Representative ofthe alkanoylanilides of Formula I thus formed are:

2'[2-(1-methyl-2-piperidyl)ethyl]acetanilide,

4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-acetanilide,

2'-[2-(1-n-butyl-2-piperidyl)ethyl]acetanilide,

2'-[2-(5-ethyl-1-methyl-2-piperidyl)ethyl]acetanilide,

N,n-diethyl-6-(o-acetamidophenethyl)-1-methylpiperidine-3-carboxamide,

2'-[2-(1-methyl-2-piperidyl)ethyl]butyranilide,

2'-[2-(1-methyl-2-piperidyl)ethyl]-2-methylpropionanilide,

4'-n-butoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]proprionanilide.

Acid hydrolysis of the formanilides of Formula VII or the analogousalkanoylanilides provide o-aminophenethylpiperidine intermediates ofFormula II wherein R¹ is hydrogen. Representative ofo-aminophenethylpiperidines which can be obtained in this manner are:

2-(o-aminophenethyl)-1-methylpiperidine,

2-(o-aminophenethyl)-1,5-dimethylpiperidine,

2-(o-aminophenethyl)-5-ethyl-1-methylpiperidine,

2-(o-aminophenethyl)-5-n-butyl-1-methylpiperidine,

2-(o-aminophenethyl)-1-isopropylpiperidine,

2-(o-aminophenethyl)-1-n-butylpiperidine,

2-(2-amino-5-methoxyphenethyl)-1-methylpiperidine,

2-(2-amino-5-n-butoxyphenethyl)-1-methylpiperidine,

2-(2-amino-5-isopropoxyphenethyl)-1-methylpiperidine,

6-(o-aminophenethyl)-N,N-dimethyl-1-methylpiperidine-3-carboxamide,

6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide,

6-(o-aminophenethyl)-N,N-di-n-butyl-1-methylpiperidine-3-carboxamide,

6-(2-amino-5-methoxyphenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide.

Reduction of some of the compounds of Formula VII with lithium aluminumhydride provide o-aminophenethylpiperidine intermediates of Formula IIwherein R¹ is alkyl. Representative ofo-(N-alkylaminophenethyl)piperidines which can be obtained in thismanner are:

2-(o-methylaminophenethyl)-1-methylpiperidine,

2-(o-methylaminophenethyl)-1,5-dimethylpiperidine,

2-(o-methylaminophenethyl)-5-ethyl-1-methylpiperidine,

2-(o-methylaminophenethyl)-5-n-butyl-1-methylpiperidine,

2-(o-methylaminophenethyl)-1-isopropylpiperidine,

2-(o-methylaminophenethyl)-1-n-butylpiperidine,

2-(2-methylamino-5-methoxyphenethyl)-1-methylpiperidine,

2-(2-methylamino-5-n-butoxyphenethyl)-1-methylpiperidine,

2-(2-methylamino-5-isopropoxyphenethyl)-1-methylpiperidine,

2-(o-ethylaminophenethyl)-1-methylpiperidine,

2-(2-ethylamino-5-methoxyphenethyl)-1-methylpiperidine,

2-(2-ethylaminophenethyl)-1-n-butylpiperidine,

2-(2-ethylaminophenethyl)-5-ethyl-1-methylpiperidine,

2-(2-n-butylaminophenethyl)-1-methylpiperidine,

2-(2-isobutylaminophenethyl)-1-methylpiperidine,

2-(2-n-propylamino-5-n-butoxyphenethyl)-1-methylpiperidine.

An alternate method for the preparation of compounds of Formula IIwherein R¹ is hydrogen is depicted in Equation 6. ##STR12##

Pyridinium iodides of Formula VIII prepared from the correspondingaromatic aldehyde and the 2-alkylpyridinium salt according to the methodof L. Horwitz, J. Org. Chem., 21, 1039 (1956) are reduced according tothe method of A. P. Phillips, J. Am. Chem. Soc., 72, 1850 (1950).Preferably the catalytic reduction is carried out employing a platinumcatalyst in methanol solution.

An alternate method for the preparation of compounds of Formula IIwherein R¹ is alkyl is depicted in Equation 7. ##STR13##

Reductive alkylation of o-aminiophenethylpiperidines of Formula X withan aldehyde such as acetaldehyde, propionaldehyde, n-butyraldehyde,isobutryaldehyde, or a ketone such as acetone or butanone provide R¹-aminophenethylpiperidines of Formula XI. This method is well known tothose skilled in the art, refer to Synethetic Organic Chemistry, Wagnerand Zook, Wiley, 1953, page 662.

Compounds of Formula I and Formula XII wherein R³ and R⁸ are hydrogen,lower alkyl, or R⁵ or R⁹ are isonipecotoyl are obtained by catalyticreduction of the corresponding pyridyl compounds. For example, reductionof 2'-[2-(2-pyridyl)ethyl]-p-anisanilide employing a palladium on carboncatalyst provides 2'-[-2-( 2-piperidyl)ethyl]-p-anisanilide. Similarly,reduction of 2'-[2-(1-methyl-2-piperidyl)ethyl]isonicotanilide affords2'-[2-(1-methyl-2-piperidyl)ethyl]isonipecotoicanilide.

Compounds of Formula XII (illustrated by Formula XV) wherein thedivalent radical A is ##STR14## and R⁸ is lower alkyl can also beobtained by reaction of an o-formylanilide of Formula XIII with a2-(N-R⁸ -2-piperidyl)ethyl magnesium chloride of Formula XIV as depictedby Equation 8. ##STR15##

The following examples illustrate the best mode contemplated forcarrying out the present invention. They are merely illustrative and arenot to be construed as limiting the scope of the claims in any mannerwhatsoever.

EXAMPLES OF SPECIFIC EMBODIMENTS Example 1

2-(o-Aminophenethyl)-1-methylpiperidine

A suspension of 2-(o-nitrostyryl)-1-methylpyridinium iodide (40.5 mg.,0.11 mole) prepared according to the method of L. Horwitz, J. Org.Chem., 21, 1039 (1956) in 200 ml. of ethanol is hydrogenated in a Parrhydrogenation apparatus employing 0.3 g. of platinum oxide catalystwhile maintaining a reaction temperature of from about 50° to 75° C.When the hydrogen uptake ceases (about 3 hours), the reduction mixtureis filtered, the filtrate evaporated and the resulting residue taken upin 500 ml. of water. The aqueous solution is basified with 40% sodiumhydroxide and extracted with several 200 ml. portions of ether. Etherealextracts are combined, washed with water, dried over magnesium sulfate,and the ether evaporated. Distillation of the resiude thus obtainedprovides 20.8 g. (87% yield) of 2-(o-aminophenethyl)-1-methylpiperidinebase having a boiling point of 121°-125° C. at 0.04 mm.

Analysis. Calcd. for C₁₄ H₂₂ N₂ : C, 77.01; H, 10.16; N, 12.83. Found:C, 76.68; H, 9.83; N, 12.76.

Treating the base with ethanolic hydrogen chloride in ethanol provides2-(o-aminophenethyl)-1-methylpiperidine dihydrochloride (crystallizedfrom methanol-isopropyl ether), m.p. 268.5°-271.5° C. (corr.).

Anaylsis. Calcd. for C₁₄ H₂₄ Cl.sub. 2 N₂ : C, 57.73; H, 8.31; N, 9.62.Found: C, 57.67; H, 8.22; N, 9.60.

2-(o-Aminophenethyl)-1-methylpiperidine has antiarrhythmic propertieshaving an EC₅₀ of 44 microgram per milliliter in the hereinabovedescribed rabbit atrium test.

EXAMPLE 2 2-(o-Methylaminophenethyl)-1-methylpiperidine

a. 2-(o-Aminophenethyl)pyridine

A solution of 2-(o-nitrostyryl)pyridine (94.3 g., 0.42 mole) in 400 ml.of ethanol is reduced on a Parr hydrogenation apparatus employing 2 g.of 10% palladium on carbon catalyst to provide2-(o-aminophenethyl)pyridine, m.p. 59°-61° C. The isolation of thepyridine product is carried out in the usual manner by collecting thecatalyst and evaporating the ethanolic solvent.

b. 2-o(Formamidophenethyl)pyridine

An aceticformic anhydride mixture is prepared by mixing acetic anhydride(140 ml.) and formic acid (70 ml.). To this mixture,2-(o-aminophenethyl)pyridine (59 g., 0.3 mole) is added in one portionwith vigorous stirring at 25° C. After 15 minutes the solution isdiluted with 450 ml. of water and concentrated in vacuo. The resultingresidue is taken up in 1 liter of water and made basic with 50% sodiumhydroxide. The basified solution is extracted with chloroform, thechloroform extract washed with water, dried over magnesium sulfate andthe chloroform solvent evaporated. Crystallization of the residue fromisopropyl acetate provides 57 g. (83% yield) of2-(o-formamidophenethyl)pyridine melting at 78°-81° C. (uncorrected). Ananalytical sample (from isopropyl acetate) has a melting point of83°-83.5° C. (corr.).

Analysis. Calcd. for C₁₄ H₁₄ N₂ O: C, 74.31; H, 6.24; N, 12.38. Found:C, 74.56; H, 6.25; N, 12.45.

c. 2 -(o-Formamidophenethyl)-1-methylpyridinium iodide

A solution of 2-(o-formamidophenethyl)pyridine (55 g., 0.243 mole) andmethyl iodide (38 g., 0.268 mole) in 500 ml. of acetone is refluxed for20 hours. The mixture is cooled at 5° C. and filtered to provide 82 g.(92%) of the pyridinium iodide having melting point of 199.5°-201.5° C.

Analysis: Calcd. for C₁₅ H₁₇ IN₂ O: C, 48.92; H, 4.65; N, 7.61. Found:C, 48.74; H, 4.83; N, 7.65.

d. 2'-[2-(1-Methyl-2-piperidyl)ethyl]formanilide

Reduction of 2-(o-formamidophenethyl)-1-methylpyridinium iodide asdescribed in Example 1 for 2-(o-nitrostyryl)-1-methylpyridinium iodideprovides 2'-[2-(1-methyl-2-piperidyl)-ethyl]formanilide which ispurified by crystallization from isopropyl ether, (79% yield) m.p.81°-84.5° C. (corr.).

Analysis. Calcd. for C₁₅ H₂₂ N₂ O: C, 73.13; H, 9.00; N, 11.37. Found:C, 73.12; H, 8.75; N, 11.31.

e. 2-(o-Methylaminophenethyl)-1-methylpiperidine

A solution of 2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide (20 g.,0.0815 mole) in 100 ml. of tetrahydrofuran is added dropwise to astirred mixture of lithium aluminum hydride (4.4 g., 0.11 mole) in 100ml. of tetrahydrofuran. The mixture is refluxed for 75 minutes, cooledand hydrolyzed by the sequential addition of 4.4 ml. of water, 4.4 ml.of 15% sodium hydroxide and then 13.2 ml. of water. The hydrolyzedmixture is filtered, the filter cake washed with a 50 ml. portion oftetrahydrofuran and the filtrate concentrated in vacuo. The residue thusobtained is distilled to provide 16.6 g. of2-(o-methylaminophenethyl)-1-methylpiperidine having a boiling point of150°-155° C. at 0.05 mm. Hg.

EXAMPLE 3 2-(2-Amino-5-methoxyphenethyl)-1-methylpiperidine

a. 2'-(2-Amino-5-methoxyphenethyl)pyridine

Reduction of 2-(2-nitro-5-methoxystyryl)pyridine as described in Example2 (a) for 2-(o-nitrostyryl)pyridine provides2-(2-amino-5-methoxyphenethyl)pyridine having a melting point of77.5°-78.5° C. (corr.) as the monohydrate obtained by crystallizationfrom isopropyl acetate-ethanol-water.

Anaylsis. Calcd. for C₁₄ H₁₆ N₂ O.H₂ O: C, 68.27; H, 7.37; N, 11.37.Found: C, 68.04; H, 7.30; N, 11.30.

b. 2-(2-Formamido-5-methoxyphenethyl)pyridine

Formylation of 2-(2-amino-5-methoxyphenethyl)pyridine as described inExample 2 (b) for 2-(o-aminophenethyl)pyridine provides a 71% yield of2-(2-formamido- 5-methoxyphenethyl)-pyridine. An analytical sampleobtained by crystallization from isopropyl acetate has a melting pointof 93.5°-94° C. (corr.).

Analysis. Calcd. for C₁₅ H₁₆ N₂ O₂ : C, 70.29; H, 6.29; N, 10.93. Found:C, 70.28; H, 6.51; N, 10.98.

c. 2-(2-Formamido-5-methoxyphenethyl)-1-methylpyridinium iodide

The pyridinium iodide is obtained by treating2-(2-formamido-5-methoxyphenethyl)pyridine with methyl iodide accordingto the procedure described in Example 2 (c) for2-(o-formamidophenethyl)pyridine. Analytically pure2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide is obtainedin a yield of 95% and has a melting point of 184°-186.5° C. (corr.).

Analysis. Calcd. for C₁₆ H₁₉ IN₂ O₂ : C, 48.25; H, 4.81; N, 7.04. Found:C, 48.18; H, 4.84; N, 7.16.

d. 2-(2-Amino-5-methoxyphenethyl)-1-methylpiperidine

Catalytic reduction of2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide asdescribed in Example 1 for 2-(o-nitrostyryl)-1-methylpyridinium iodideprovides 2-(2-formamido-5-methoxyphenethyl)-1-methylpiperidine. Thismaterial is deformylated in 1N methanolic hydrogen chloride providing2-(2-amino-5-methoxyphenethyl)-1-methylpiperidine.

Another method of preparing2-(2-formamido-5-methoxyphenethyl)-1-methylpiperidine is to reduce2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide first withsodium borohydride to provide2-(2-formamido-5-methoxyphenethyl)-1-methyltetrahydropyridine which isthen reduced catalytically with palladium on carbon. This procedure isdescribed in Example 4 (d).

EXAMPLE 46-(o-Aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide(Racemate A and Racemate B)

a. N,N-Diethyl-6-(o-nitrostyryl)nicotinamide

Reaction of o-nitrobenzaldehyde (41.7 g., 0.276 mole) withN,N-diethyl-6-methylnicotinamide (53.1 g., 0.276 mole) in the presenceof acetic anhydride (56.3 g., 0.552 mole) according to the method of L.Horwitz, J. Org. Chem., 21, 1039 (1956) provides 67.4 g. (75%) ofN,N-diethyl-6-(o-nitrostyryl)-nicotinamide. Crystallization fromacetonitrile affords the analytically pure nicotinamide having a meltingpoint of 145°-147° C. (corr.).

Analysis. Calcd. for C₁₈ H₁₉ N₃ O₃ : C, 66.44; H, 5.89; N, 12.92. Found:C, 66.62; H, 6.01; N, 12.68.

b. 6-(o-Aminophenethyl)-N,N-diethylnicotinamideN,N-diethyl-6-(o-nitrostyryl)nicotinamide (16.3 g., 0.05 mole) reducedin 150 ml. of ethanol employing 0.1 g. of 10% palladium on carboncatalyst according to the procedure described in Example 2 (a) for2-(o-aminophenethyl)pyridine provides6-(o-aminophenethyl)-N,N-diethylnicotinamide base. Addition of ethanolichydrogen chloride to the nicotinamide base in ethanol provides6-(o-aminophenethyl)-N,N-diethylnicotinamide dihydrochloride, m.p.224°-226° C. (corr.).

Analysis. Calcd. for C₁₈ H₂₅ Cl.sub. 2 N₃ O: C, 58.38; H, 6.80; N,11.35. Found: C, 58.21; H, 6.86; N, 11.31.

c. 5-Diethylcarbamyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide

Formylation of 6-(o-aminophenethyl)-N,N-diethylnicotinamide as describedin Example 2 (b) for 2-(o-formamidophenethyl)pyridine provides6-(o-formamidophenethyl)-N,N-diethylnicotinamide which is thenmethylated as described in Example 2 (c) for2-(o-formamidophenethyl)-1-methylpyridinium iodide to provide5-diethylcarbamyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide.This product is employed in the following step without furtherpurification.

d.N,N-Diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide.

A 50% sodium hydroxide solution (9.6 g., 0.12 mole) in 45 ml. of wateris added to a solution of 5-diethylcarbamyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide (46.7 g., 0.1 mole)in 300 ml. of methanol. Sodium borohydride (4.56 g., 0.12 mole) is addedin portions with stirring to the reaction mixture. After 2 hr. themixture is evaporated and water (500 ml.) is added to the resultingresidue. This mixture is extracted with ether, the ethereal extractswashed with water, dried over magnesium sulfate and the etherevaporated. The resulting residue consisting ofN,N-diethyl-6-(o-formamidophenethyl)-1-methyltetrahydropyridine-3-carboxamidehydrogenated in a Parr apparatus in 200 ml. of ethanol employing 4 g. of10% palladium on carbon as the catalyst at a temperature of 50° -70° C.providesN,N-diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide.

e. 6-(o-Aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide

N,N-Diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide ishydrolyzed to6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide asdescribed in Example 3 (d) for2-(o-methylaminophenethyl)-1-methylpiperidine.

f. Separation of6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide intoRacemate A and Racemate B

Crude 6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboximide(11 g.) containing a 1:1 mixture of Racemate A and Racemate B which isobtained in the preceding steps by hydrolysis ofN,N-diethyl-6-(o-formamidophenethyl)-1 -methylpiperidine-3-carboxamideis dissolved in 50 ml. of benzene and loaded on a 4 cm. diameterchromatographic column packed to a height of 45 cm. with silica gel (300g., 100-200 mesh). The column is eluted with the following solventcombinations and 100 ml. fractions collected: fractions 1-2, benzene;fractions 3-39, ethyl acetate-ethanol 7:3 plus 0.2% of 58% ammoniumhydroxide; fractions 40-70, ethyl acetate-ethanol 1:1 plus 0.5% of 58%ammonium hydroxide; fractions 71-78, ethanol plus 0.5% of 58% ammoniumhydroxide. Fractions 13 through 44 are combined and concentrated toprovide about 4 to 5 g. of pure Racemate A as an oil. Evaporation ofcombined fractions 55-72 provides 3.2 g. of pure Racemate B as an oil.

EXAMPLE 5 2-(o-Aminophenethyl)-5-ethyl-1-methylpiperidine (Racemate Aand Racemate B)

a. 5-Ethyl-2-(o-nitrostyryl)pyridine

Reaction of o-nitrobenzaldehyde (100 g., 0.66 mole) with5-ethyl-2-methylpyridine (80 g., 0.66 mole) in the presence of aceticanhydride (135 g., 1.32 mole) according to the method of L. Horwitz, J.Org. Chem., 21, 1039 (1956) provides 54.4 g. (32%) of5-ethyl-2-(o-nitrostyryl)pyridine. An analytical sample obtained bycrystallization from isopropyl ether has a melting point of 52.5° -54.5°C. (corr.).

Analysis. Calcd. for C₁₅ H₁₄ N₂ O₂ : C, 70.85; H, 5.55; N, 11.02. Found:C, 71.01; H, 5.40; N, 10.96.

b. 2-(o-Aminophenethyl)-5-ethylpyridine

Reduction of 5-ethyl-2-(o-nitrostyryl)pyridine as described in Example 2(a) for 2-(o-nitrostyryl)pyridine provides2-(o-aminophenethyl)-5-ethylpyridine having a melting point of 52.5°-53.5° C. (corr.) when crystallized from isopropyl ether-heptane.

c. 5-Ethyl-2-(o-formamidophenethyl)pyridine

Reaction of 2-(o-aminophenethyl)-5 -ethylpyridine with acetic anhydrideand formic acid according to the procedure described in Example 2 (b)for 2-(o-aminophenethyl)pyridine provides the formylated product5-ethyl-2-(o-formamidophenethyl)pyridine which can be crystallized fromisopropyl ether, m.p. 62° -63.5° C. (corr.).

Analysis. Calcd. for C₁₆ H₁₈ N₂ O: C, 75.56; H, 7.13; N, 11.02. Found:C, 75.53; H, 7.07; N, 10.96.

d. 5-Ethyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide

Reaction of 5-ethyl-2-(o-formamidophenethyl)pyridine with methyl iodidein acetone according to the procedure of Example 2 (c) for2-(o-formamidophenethyl)pyridine provides a 74% yield of analyticallypure 5-ethyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide having amelting point of 134° -136.5° C.

Analysis. Calcd. for C₁₇ H₂₁ IN₂ O: C, 51.53; H, 5.34; N, 7.07. Found: C51.79; H, 5.35; N, 6.84.

e. 5-Ethyl-2-(o-formamidophenethyl)-1-methylpiperidine

Reduction of 5-ethyl-2-(o-formamidophenethyl)1-methylpyridinium iodideas described in Example 4 (d) for the correspondingN,N-diethyl-3-carboxamide provides5-ethyl2-(o-formamidophenethyl)-1-methypiperidine comprised of a 1:1mixture of Racemate A and Racemate B.

f. Separation of 2-(o-aminophenethyl)-5-ethyl-1-methylpiperidine intoRacemate A and Racemate B

Racemate B is isolated from the Racemate A and B mixture of5-ethyl-2-(o-formamidophenethyl)-1-methylpiperidine by treating 19.8 g.of the mixture with oxalic acid (9.15 g., 0.0723 mole) dihydrate in 200ml. of ethanol which provides 14.3 g. of a crystalline solid (oxalicacid salt), m.p. 166° -170° C. Crystallization of this material fromethanol selectively provides 8.2 g., of the Racemate B of2-(o-formamidophenethyl)-5-ethyl-1-methylpiperidine as the oxalic acidsalt, m.p. 174° -176° C.

Analysis. Calcd. for C₁₇ H₂₆ N₂ O.C₂ H₂ O₄ : C, 62.62; H, 7.74; N, 7.69.Found: C, 62.45; H, 7.46; N, 7.76.

The oxalic acid salt of2-(o-formamidophenethyl)-5-ethyl-1-methylpiperidine (Racemate B) isconverted to the free base by treatment with potassium hydroxide.

Hydrolysis of the formamido free base is carried out by stirring with125 ml. of 1N methanolic hydrogen chloride for 24 hr. Concentration ofthe methanolic mixture in vacuo provides a residue which is taken up inwater and made basic with 50% sodium hydroxide. Extraction of thebasified mixture with ether and concentration of the ether extractprovides 5.5 g. of 2-(o-aminophenethyl)-5-ethyl-1-methylpiperidine BRacemate free base.

The oxalic acid salt mother liquor remaining from isolation of2-(o-formamidophenethyl)-5-ethyl-1-methylpiperidine (Racemate B) whichis enriched in 2-(o-formamidophenethyl)-5-ethyl-1-methylpiperidine(Racemate A) is converted to the free base. Deformylation of 6.7 g. ofthe 5-ethyl-2-(o-formamidephenethyl)-1-methylpiperidine base in 250 ml.of 1N methanolic hydrogen chloride provides 5.1 g. of a hydrochloricacid salt, m.p. 235° -238° C. This salt selectively crystallized fromethanol-isopropyl ether provides 4.4 g. of material which is thenconverted to the free base providing 3.3 g. of2-o-aminophenethyl)-5-ethyl-1-methylpiperidine (Racemate A) as an oil.

EXAMPLE 6 2 -(o-Isopropylaminophenethyl)-1 -methylpiperidine

A mixture of 0.01 mole of 2-(o-aminophenethyl)-1 -methylpiperidine, 2.40ml. (0.03 mole) of acetone, 0.63 ml. (0.01 mole) of acetic acid, and0.25 g. of platinum oxide in 100 ml. of absolute ethanol is hydrogenatedat 40 p.s.i. until 0.01 mole of hydrogen has been absorbed. The reactionmixture is filtered, the filtrate acidified with ethanolic hydrogenchloride and evaporated to dryness at reduced pressure to provide2-(o-isopropylaminophenethyl)-1-methylpiperidine as a dihydrochloridesalt. Alternatively, the reaction mixture can be filtered, andconcentrated to provide the 2'--(o-isopropylaminophenethyl)-1-methylpiperidine as an acetate salt.

In a similar manner by employing other o-aminophenethylpiperidines,other 2-(o-alkylaminophenethyl)-1-methylpiperidines can be prepared.

The free base is isolated from either the hydrochloric acid or acetateaddition salt by standard procedures well known to those skilled in theart. For example, the dihydrochloride salt of2-(o-isopropylaminophenethyl)-1-methylpiperidine is dissolved in water,neutralized with sodium hydroxide. The free base is extracted from themixture with an immiscible solvent such as ether or ethyl acetate.Concentration of the extracted mixture provides the isolated free base.

EXAMPLE 7-24. Additional o-aminophenethylpiperidines

By employing the procedures of Example 1-6, othero-aminophenethylpiperidines which are useful for the preparation of thecompounds of Formula I are obtained. Representative of theo-aminophenethylpiperidines of the present invention are listed in TableI, along with starting materials and reference to the experiment numberwherein the procedure is described. It will be readily apparent to thoseskilled in the art that in many instances, a particularo-aminophenethylpiperidine can be prepared by more than one procedure.Thus, for example 2-(o-aminophenethyl)-1-methylpiperidine obtained inExample 1 can be prepared according to the method of Example 3 byhydrolyzing 2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide which isobtained from 2-(o-nitrostyryl)piperidine.

                                      TABLE I                                     __________________________________________________________________________    ADDITIONAL o-AMINOPHENETHYLPIPERIDINES                                        __________________________________________________________________________     ##STR16##                                                                                                                         Procedure                Example                                                                            R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                             R.sup.4      Starting Materials                                                                             (Example                 __________________________________________________________________________                                                         No.)                      7   H     H     CH.sub.3                                                                            CH.sub.3                                                                              2,5-dimethylpyridine and                                                                            5-nitro-                                                benzaldehyde                                    8   H     H     CH.sub.3                                                                            n-C.sub.4 H.sub.9                                                                     5-n-butyl-2-methylpyridine                                                                          5nd                                                     o-nitrobenzaldehyde                             9   H     H     CH.sub.3                                                                            (CH.sub.3).sub.2 CH                                                                   5-isopropyl-2-methylpyridine                                                                        5nd                                                     o-nitrobenzaldehyde                            10   H     (CH.sub.3).sub.2 CHO                                                                CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                    5-isopropyl-2-methylpyridine                                                                        5nd                                                     2-nitro-5-isopropoxybenzaldehyde               11   H     H     CH.sub.3                                                                            CON(CH.sub.3).sub.2                                                                   o-nitrobenzaldehyde and N,N-dimethyl-                                                               4                                                       6-methylnicotinamide                           12   H     H     CH.sub.3                                                                            CON(n-C.sub.4 H.sub.9).sub.2                                                          o-nitrobenzaldehyde and N,N-di(n-                                                                   4                                                       butyl)-6-methylnicotinamide                    13   H     CH.sub.3 O                                                                          CH.sub.3                                                                            CH.sub.3                                                                              2,5-dimethylpyridine and                                                                            5-nitro-                                                5-methoxybenzaldehyde                          14   H     n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                            H       2-methylpyridine, 2-nitro-5-n-butoxy-                                                               3                                                       benzaldehyde and methyl iodide                 15   H     H     n-C.sub.4 H.sub.9                                                                   H       2-methylpyridine, o-nitrobenzaldehyde                                                               3                                                       and 1-iodobutane                               16   H     H     (CH.sub.3).sub.3 C                                                                  H       2-methylpyridine, o-nitrobenzaldehyde                                                               3                                                       and 1-iodo-2-methylpropane                     17   H     CH.sub.3 O                                                                          (CH.sub.3).sub.2 CH                                                                 H       2-methylpyridine, 2-nitro-5-methoxy-                                                                3                                                       benzaldehyde and 2-iodopropane                 18   CH.sub.3                                                                            H     CH.sub.3                                                                            CH.sub.3                                                                              2,5-dimethylpyridine, o-nitrobenz-                                                                  2                                                       aldehyde                                       19   n-C.sub.4 H.sub.9                                                                   H     CH.sub.3                                                                            H       2-methylpyridine, o-nitrobenzaldehyde                                                               2                                                       and butyryl chloride                           20   CH.sub.3                                                                            CH.sub.3 O                                                                          CH.sub.3                                                                            H       2-methylpyridine and 2-nitro-5-                                                                     2                                                       methoxybenzaldehyde                            21   H     H     (CH.sub.3).sub.2 CH                                                                 H       1-isopropyl-2-methylpyridinium                                                                      1                                                       iodide and o-nitrobenzaldehyde                 22   C.sub.2 H.sub.5                                                                     H     CH.sub.3                                                                            H       2-(o-aminophenethyl)-1-methylpiperidine                                                             6                                                       and acetaldehyde                               23   (CH.sub.3).sub.2 CH                                                                 CH.sub.3 O                                                                          CH.sub.3                                                                            H       2-(2-amino-5-methoxyphenethyl)-1-                                                                   6                                                       methylpiperidine and acetone                   24   CH.sub.3                                                                            CH.sub.3 O                                                                          CH.sub.3                                                                            C.sub.2 H.sub.5                                                                       5-ethyl-2-methylpyridine and                                                                        2-nitro-                                                5-methoxybenzaldehyde                          __________________________________________________________________________

EXAMPLE 25 2'-[2-(1-Methyl-2-piperidyl)ethyl]-cinnamanilide

Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of2-(o-aminophenethyl)-1-methylpiperidine (7.8 g., 0.036 mole) in 100 ml.of pyridine in one portion with vigorous stirring. Stirring is continuedfor 3 hours and the pyridine solution is then concentrated in vacuo. Theresulting residue is taken up in 150 ml. of water and made basic with40% sodium hydroxide. The basified solution is extracted with several200 ml. portions of ether, which are combined, washed with water, driedover magnesium sulfate and the ether solvent evaporated. The residuethus obtained crystallizes and is further purified by crystallizing fromisopropyl ether providing 8.7 g. (70% yield) of analytically pure2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide melting at 101.5°-103.5° C. (corr.).

Analysis. Calcd. for C₂₃ H₂₈ N₂ O: C, 79.27; H, 8.10; N, 8.04. Found: C,79.24; H, 8.35; N, 8.09.

EXAMPLE 26 2'-[2-(1 -Methyl-2-piperidyl)ethyl]-α-methylcinnamanilidemucate

By substituting a molar equivalent of α-methylcinnamoyl chloride in lieuof cinnamoyl chloride in Example 25, the substituted phenethylpiperidinefree base is obtained. The mucate salt is prepared by dissolving thefree base in methanol and adding mucic acid to the methanolic solutionuntil the solid mucic acid no longer dissolves. Undissolved mucic acidis removed by filtering and the filtrate concentrated. The residue whichremains is crystallized from ethanol-ethyl acetate to provideanalytically pure2'-[2-(1methyl-2-piperidyl)ethyl]-α-methylcinnamanilide mucate having amelting point of 154.5° -156.5° C. (dec.)(corr.).

Analysis. Calcd. for C₂₄ H₃₀ N₂₀.1/2C₆ H₁₀ O₈ : C, 69.35; H, 7.54; N,5.99. Found: C, 69.25; H, 7.59; N, 5.89.

EXAMPLE 27 N-Methyl-2'-[2-(1-methyl-2-piperidyl)-ethyl]cinnamanilidemucate

By substituting a molar equivalent of2-(o-methylaminophenethyl)-1-methylpiperidine in lieu of2-(o-aminophenethyl)-1-methylpiperidine in Example 25,N-methyl2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide is obtained. Themucate salt is prepared according to Example 26, and is crystallizedfrom methanol to provide analytically pureN-methyl-2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide mucate in 38%yield having a melting point of 174° -176° C. (corr.).

Analysis. Calcd. for C₂₄ H₃₀ N₂ O.1/2C₆ H₁₀ O₈ : C, 69.35; H, 7.54; N,5.99. Found: C, 69.38; H, 7.56; N, 5.97.

EXAMPLE 28 4'-Methoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]cinnamanilide

By substituting a molar equivalent of2-(2-amino-5-methoxyphenethyl)-1-methylpiperidine in lieu of2-(-aminophenethyl)-1-methylpiperidine in Example 25, thephenethylpiperidine free base is obtained. Analytically pure4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide is obtainedby crystallizing the crude free base from isopropyl acetate and has amelting point of 126.5° -127.5° C. (corr.).

Analysis Calcd. for C₂₄ H₃₀ N₂ O₂ : C, 76,15; H, 7.99; N, 7.40. Found:C, 76.37; H, 7.93; N, 7.36.

EXAMPLE 296-(o-Cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamidemucate (Racemate A)

Reaction of the Racemate A of 6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide (5.1 g., 0.16 mole) obtained in Example4 (f) with cinnamoyl chloride (3.2 g., 0.19 mole) in 70 ml. of pyridineaccording to the method of Example 25 provides 7.3 g. of the freepiperidine carboxamide base. The free base reacted with mucic acid inboiling methanol provides the mucate salt. This methanol soluble mucatesalt is dissolved in methanol and precipitated therefrom by the additionof isopropyl ether. Crysatllization from ethanol-isopropyl etherprovides 3.4 g. of6-(o-cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboximaidemucate hydrate with water, m.p. 79° -110° C.

Analysis Calcd. for C₂₈ H₃₇ N₃ O₂.1/2C₆ H₁₀ O₈.1/2H₂ O: C, 64.45; H,7.50; N, 7.27. Found: C, 64.38; H, 7.69; N, 6.89.

Crystallization of this material from methanol provides a methanolsolvated mucate salt. The methanol solvate is removed by drying at 82°C. in vacuo for 24 hr. to provide a methanol free product having amelting point of 117° -120° C. (corr.).

EXAMPLE 306-(o-Cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamidecinnamate (Racemate B)

Reaction of the Racemate B of6-(o-aminophenethyl)-N,N-diethyl1-methylpiperidine-3-carboxamide (4.1g., 0.13 mole) obtained in Example 4 (f) with cinnamoyl chloride (2.6g., 0.015 mole) in 40 ml. of pyridine according to the method of Example25 provides 6.0 g., of the free base. The free base is taken up in 100ml. of ethanol and treated with cinnamic acid (1.98 g., 0.013 mole). Thecinnamic acid salt of6-(o-cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide isprecipitated from the ethanolic solution by the addition of isopropylether to provide 5.3 g. of solid with a melting point of 156° -160° C.

Crystallization from methanol-isopropyl ether provides analytically pureRacemate B product which has a melting point of 158° -164° C. (corr.).

Analysis. Calcd. for C₂₈ H₃₇ N₃ O₂.C₉ H₈ O₂ : C, 74.59; H, 7.61; N,7.05. Found: C, 74.33; H, 7.89; N, 7.07.

EXAMPLE 31 2'-[2-(5-Ethyl-1-methyl-2-piperidyl)-ethyl]cinnamanilidehydrochloride (Racemate A)

Reaction of 2'-(o-aminophenethyl)-5-ethyl-1-methylpiperidine (3.3 g.,0.0134 mole) obtained in Example 5 (f) with cinnamoyl chloride (2.7 g.,0.016 mole) in 50 ml. of pyridine according to the method of Example 25provides 4.2 g. of the hydrochloric salt, m.p. 184° -186° C.Crystallization of the salt from isopropanol affords 3.6 g., (65%) of2'-[2-(5-ethyl-1-methyl-2-piperidyl)-ethyl]cinnamaldehyde hydrochloride(Racemate A), m.p. 184° -187° C. (corr.).

Analysis. Calcd. for C₂₅ H₃₃ ClN₂ O: C, 72.70; H, 8.05; N, 6.78. Found:C, 72.82; H, 8.37; N, 6.45.

EXAMPLE 32 2'-[2-(5-ethyl-1-methyl-2-piperidyl)-ethyl]cinnamanilidehydrate (Racemate B)

Racemate B of 5-ethyl-2'-(o-formamidophenethyl)-1-methylpiperidine freebase (5.5 g., 0.0224 mole) obtained in Example 5 (f) reacted withcinnamoyl chloride (4.1 g., 0.0246 mole) in 75 ml. of pyridine accordingto the method of Example 25 provides2'-[2-(5-ethyl-1-methyl-2-piperidyl)ethy]cinnamanilide (Racemate B).This substance is purified by crystallization from acetone containing atrace of water and yields 3.4 g. of2'-[2-(5-ethyl-1-methyl-2-piperidyl)ethyl]cinnamanilide hydrate, m.p.91° -98° C (corr.).

Analysis. Calcd. for C₂₅ H₃₂ N₂ O.H₂ O: C, 76.10; H, 8.69; N, 7.10; H₂O, 4.57. Found: C, 76,24; H, 8.47; N, 7.19; H₂ O, 4.29.

EXAMPLES 33-54 Additional Cinnamanilides and formanilides

The cinnamanilides and formanilides listed in Table II are prepared fromthe specified reactants according to the procedures described inExamples 25-32 as will be clear to those skilled in the art.

                                      TABLE II                                    __________________________________________________________________________    ADDITIONAL CINNAMANILIDES AND FORMANILIDES                                    __________________________________________________________________________     ##STR17##                                                                    Example                                                                            R.sup.1                                                                           R.sup.2                                                                             R.sup.3                                                                             R.sup.4 R.sup.5 Reactants                                __________________________________________________________________________    33   C.sub.2 H.sub.5                                                                   n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                            H       CHCHφ                                                                             2-(2-ethylamino-5-n-butoxyphenethyl)-                                         1-                                                                            methylpiperidine and cinnamoyl                                                chloride                                 34   C.sub.2 H.sub.5                                                                   n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                            H       H       2-(2-ethylamino-5-n-butoxyphenethyl)-                                         1-                                                                            methylpiperidine and formic                                                   acid-acetic                                                                   anhydride                                35   CH.sub.3                                                                          H     n-C.sub.4 H.sub.9                                                                   H       CHCHφ                                                                             2-(o-methylaminophenethyl)-1-n-butyl-                                         .                                                                             piperidine and cinnamoyl chloride        36   CH.sub.3                                                                          H     (CH.sub.3).sub.2 CH                                                                 H       H       2-(o-methylaminophenethyl)-1-isopropy                                         l-                                                                            piperidine and formic acid-acetic                                             anhydride                                37   n-C.sub.4 H.sub.9                                                                 H     CH.sub.3                                                                            H       CHCHφ                                                                             2-(2-n-butylaminophenethyl)-1-methylp                                         iperidine                                                                     and cinnamoyl chloride                   38   n-C.sub.4 H.sub.9                                                                 H     CH.sub.3                                                                            H       H       2-(2-n-butylaminophenethyl)-1-methylp                                         iperidine                                                                     and formic acid-acetic anhydride         39   H   H     CH.sub.3                                                                            CH.sub.3                                                                              CHCHφ                                                                             2-(o-aminophenethyl)-5-methyl-1-methy                                         l-                                                                            piperidine and cinnamoyl chloride        40   H   H     CH.sub.3                                                                            CH.sub.3                                                                              H       2-(o-aminophenethyl)-5-methyl-1-methy                                         l-                                                                            piperidine and formic acid-acetic                                             anhydride                                41   H   H     CH.sub.3                                                                            n-C.sub.4 H.sub.9                                                                     CHCHφ                                                                             2-(o-aminophenethyl)-5-n-butyl-1-meth                                         yl-                                                                           piperidine and cinnamoyl chloride        42   H   H     CH.sub.3                                                                            n-C.sub.4 H.sub.9                                                                     H       2-(o-aminophenethyl)-5-n-butyl-1-meth                                         yl-                                                                           piperidine and formic acid-acetic                                             anhydride                                43   H   (CH.sub.3).sub.2 CHO                                                                CH.sub.3                                                                            (CH.sub.3).sub.2 CH                                                                   CHCHφ                                                                             2-(2-amino-5-isopropoxyphenethyl)-5-                                          isopropyl-1-methylpiperidine and                                              cinnamoyl chloride                       44   H   (CH.sub.3).sub.2 CHO                                                                CH.sub.3                                                                            (CH.sub.3).sub.2 CH                                                                   H       2-(2-amino-5-isopropoxyphenethyl)-5-                                          isopropyl-1-methylpiperidine and                                              formic acid-acetic anhydride             45   H   H     CH.sub.3                                                                            CON(CH.sub.3).sub.2                                                                   CHCHφ                                                                             6-(o-aminophenethyl)-N,N-dimethyl-1-                                          methylpiperidine-3-carboxamide and                                            cinnamoyl chloride                       46   H   H     CH.sub.3                                                                            CON(CH.sub.3).sub.2                                                                   H       6-(o-aminophenethyl)-N,N-dimethyl-1-                                          methylpiperidine-3-carboxamide and                                            formic acid-acetic anhydride             47   H   H     CH.sub.3                                                                            CON(n-C.sub.4 H.sub.9).sub.2                                                          CHCHφ                                                                             6-(o-aminophenethyl)-N,N-di-n-butyl-1                                         -                                                                             methylpiperidine-3-carboxamide and                                            formic acid-acetic anhydride             48   H   H     CH.sub.3                                                                            CON(n-C.sub.4 H.sub.9).sub.2                                                          H       6-(o-aminophenethyl)-N,N-di-n-butyl-1                                         -                                                                             methylpiperidine-3-carboxamide and                                            formic acid-acetic anhydride             49   CH.sub.3                                                                          CH.sub.3 O                                                                          CH.sub.3                                                                            CON(C.sub.2 H.sub.5).sub.2                                                            CHCHφ                                                                             6-(2-methylamino-5-methoxyphenethyl)-                                         N,N-                                                                          diethyl-1-methylpiperidine-3-carboxam                                         ide                                                                           and cinnamoyl chloride                   50   CH.sub.3                                                                          CH.sub.3 O                                                                          CH.sub.3                                                                            CON(C.sub.2 H.sub.5).sub.2                                                            H       6-(2-methylamino-5-methoxyphenethyl)-                                         N,N-                                                                          diethyl-1-methylpiperidine-3-carboxam                                         ide                                                                           and formic acid-acetic anhydride         51   H   H     CH.sub.3                                                                            H                                                                                      ##STR18##                                                                            2-(o-aminophenethyl)-1-methylpiperidi                                         ne and α-ethylcinnamoyl                                                 chloride                                 52   n-C.sub.4 H.sub.9                                                                 H     CH.sub.3                                                                            H                                                                                      ##STR19##                                                                            2-(2-n-butylaminophenethyl)-1-methyl-                                          piperidine and α-ethylcinnamoy                                         l chloride                               53   H   H     CH.sub.3                                                                            H                                                                                      ##STR20##                                                                            2-(o-aminophenethyl)-1-methylpiperidi                                         ne and α-n-butylcinnamoyl                                               chloride                                 54   H   H     CH.sub.3                                                                            H                                                                                      ##STR21##                                                                            2-(o-aminophenethyl)-1-methylpiperidi                                         ne and α-isopropylcinnamoyl                                             chloride                                 __________________________________________________________________________

EXAMPLE 55 2'-[2-(1-Methyl-2-piperidyl)ethyl]-2-thiophenecarboxanilidemucate

2-Thiophenecarbonyl chloride (11.7 g., 0.08 mole) is added in oneportion to 2-(o-aminophenethyl)-1-methylpiperidine (10.0 g., 0.046 mole)in 50 ml. of pyridine with stirring. The mixture stirred for 0.5 hr. andconcentrated in vacuo provides a residue which is taken up in 50 ml. ofwater and made basic (pH 9-10) with potassium carbonate. The aqueousmixture is extracted with ether, the ethereal extract washed with waterand after drying over magnesium sulfate, concentrated to provide thethiophenecarboxanilide base.

The mucate salt is prepared by dissolving the free base in ethanol andadding mucic acid to the ethanolic solution until solid mucic acid nolonger dissolves. Insoluble mucic acid is removed by filtration and theethanolic filtrate diluted with ethyl acetate to incipient turbidity.This provides 14.0 g. of the mucate salt which crystallized fromethanol-ethyl acetate provides 6.4 g. of analytically pure2'-[2-(1-methyl-2-piperidyl)-ethyl]-2-thiophenecarboxanilide, m.p.143.5-146° C. (corr.).

Analysis. Calcd. for C₁₉ H₂₄ N₂ OS.1/2 C₆ H₁₀ O₈ : C, 60.95; H, 6.74; N,6.46; S, 7.40. Found: C, 60.83; H, 6.57; N, 6.43; S, 7.22.

EXAMPLES 56-64 Additional thiophenecarboxanilides

By substituting the appropriate 2-(o-aminophenethyl)piperidine in lieuof 2-(o-aminophenethyl)-1-methylpiperidine in Example 55, thethiophenecarboxanilides of Table III are prepared.

                                      TABLE III                                   __________________________________________________________________________    ADDITIONAL THIOPHENECARBOXANILIDES                                            __________________________________________________________________________     ##STR22##                                                                    Example                                                                            R.sup.1                                                                            R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                              Reactants                                        __________________________________________________________________________    56   CH.sub.3                                                                           H      CH.sub.3                                                                           H      2-(o-methylaminophenethyl)-1-methylpiperidine                                 and 2-thiophenecarbonyl chloride                 57   n-C.sub.4 H.sub.9                                                                  H      CH.sub.3                                                                           H      2-(2-n-butylaminophenethyl)-1-methylpiperidin                                 e -     and 2-thiophenecarbonyl chloride         58   H    CH.sub.3 O                                                                           CH.sub.3                                                                           H      2-(2-amino-5-methoxyphenethyl)-1-methylpiperi                                 dine                                                                          and 2-thiophenecarbonyl chloride                 59   H    n-C.sub.4 H.sub.9 O                                                                  CH.sub.3                                                                           H      2-(2-amino-5-n-butoxyphenethyl)-1-methylpiper                                 idine                                                                         and 2-thiophenecarbonyl chloride                 60   H    H      n-C.sub.4 H.sub.9                                                                  H      2-(o-aminophenethyl)-1-n-butylpiperidine                                      and                                                                           2-thiophenecarbonyl chloride                     61   H    H      CH.sub.3                                                                           CH.sub.3                                                                             2-(o-aminophenethyl)-5-methyl-1-methylpiperid                                 ine                                                                           and 2-thiophenecarbonyl chloride                 62   H    H      CH.sub.3                                                                           n-C.sub.4 H.sub.9                                                                    2-(o-aminophenethyl)-5-n-butyl-1-methyl-                                      piperidine and 2-thiophenecarbonyl chloride      63   H    (CH.sub.3).sub.2 CHO                                                                 CH.sub.3                                                                           H      2-(2-amino-5-isopropoxyphenethyl)-1-methyl-                                   piperidine and 2-thiophenecarbonyl chloride      64   H    H      CH.sub.3                                                                           CON(C.sub.2 H.sub.5).sub.2                                                           6-(o-aminophenethyl)-N,N-diethyl-1-methyl-                                    piperidine-3-carboxamide and 2-thiophene-                                     carbonyl chloride                                __________________________________________________________________________

EXAMPLE 65 2'-[2-(1-Methyl-2-piperidyl)ethyl]-acetanilide mucate

By substituting a molar equivalent of acetyl chloride in lieu ofcinnamoyl chloride in Example 25,2'-[2-(1-methyl-2-piperidyl(ethyl]acetanilide free base is obtained. Thecrude free base is converted to the crystalline mucate according to theprocedure of Example 26 and crystallized from ethanol to provideanalytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide mucate,m.p. 173.5-174.5° C. (corr.).

Analysis. Calcd. for C₁₆ H₂₄ N₂ O.1/2 C₆ H₁₀ O₈ : C, 62.44; H, 8.00; N,7.66. Found: C, 62.47; H, 8.29; N, 7.79.

An alternative preparation of2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide mucate is as follows.2-(o-Acetamidophenethyl)pyridine (12.6 g., 0.05 mole) obtained accordingto D. H. Hey and J. M. Osbond, J. Chem. Soc., 3170 (1949), is reactedwith methyl iodide (7.9 g., 0.055 mole) in 100 ml. of acetone accordingto the method of Example 2 (c) to provide 11.5 g. (60%) of2-(o-acetamidophenethyl)pyridinium iodide, m.p. 229.5°-231.5° C.(corr.), (crystallized from ethanol).

Analysis. Calcd. for C₁₆ H₁₉ IN₂ O; C, 50.37; H, 5.01; N, 7.33. Found:C, 49.97; H, 4.84; N, 7.22.

Reduction of 2-(o-acetamidophenethyl)pyridinium iodide in ethanolemploying platinum oxide catalyst according to the procedure of Example1 provides the piperidyl free base which is then converted to2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide mucate according toExample 26.

EXAMPLE 666-(o-Acetamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide(Racemate A and Racemate B)

Acylation of 6-(o-aminophenethyl)-N,N-diethylnicotinamide in chloroformwith acetic anhydride provides6-(o-acetamidophenethyl)-N,N-diethylnicotinamide which methylated withmethyl iodide in acetone according to the procedure of Example 2 (c)yields 2-(o-acetamidophenethyl)-5-diethylcarbamyl-1-methylpyridiniumiodide. Passing an aqueous solution of2-(o-acetamidophenethyl)-5-diethylcarbamyl-1-methylpyridinium iodidethrough a Dowex 21-K 50-100 mesh ion exchange column in the Cl⁻ formprovides 2-(o-acetamidophenethyl)-5-diethylcarbamyl-1-methylpyridiniumchloride which is isolated by concentration of the aqueous solution.

Reduction of2-(o-acetamidophenethyl)-5-diethylcarbamyl-1-methylpyridinium chloridein ethanol according to the method of Example 1 provides a mixture ofthe two racemates (Racemate A and Racemate B) of6-(o-acetamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamidewhich are chromatographically separated as follows. A chromatographiccolumn (4 cm. diameter) is packed to a height of 45 cm. with silica gel(300 g., 100-200 mesh, Davison Chemical Company, Grade 923) as a slurryin benzene. A mixture of Racemate A and B of6-(o-acetamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide(10.8 g.) is loaded on the column in 50 ml. of benzene. The following100 ml. fractions were collected. Fractions 1 to 3, benzene; fractions4-43, ethanol-ethyl acetate 3:7 + 0.2% 58% NH₄ OH; fractions 44-70,ethanolethyl acetate 1:1 + 0.5% 58% NH₄ OH; fractions 71-84, ethanol +0.5% 58% NH₄ OH. Fractions 5-36 are combined and evaporated to provide2.4 g. of chromatographically pure (thin-layer) Racemate A. Fractions55-84 are combined and evaporated to provide 5.9 g. of Racemate B.Racemates A and B are further purified by distillation in a sublimatorat 0.02 mm. Hg.

Analytical values, infrared and n.m.r. spectra are consistent forRacemate A and Racemate B.

Analysis. Calcd. for C₂₁ H₃₃ N₃ O₂ : C, 70.16; H, 9.26; N, 11.69. Found:(Racemate A) C, 70.51; H, 9.40; N, 11.82; (Racemate B) C, 70.03; H,9.44; N, 11.75.

An alternate method of preparing Racemate A and Racemate B of6-(o-acetamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamidecomprises the reaction of acetic anhydride with6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamideRacemate A and Racemate B obtained in Example 4 (f).

EXAMPLES 67-75 Additional alkanoyl anilides

The alkanoyl anilides listed in Table IV are prepared from the specifiedreactants according to the procedures of Examples 25-32 as will be clearto those skilled in the art.

                                      TABLE IV                                    __________________________________________________________________________    ADDITIONAL ALKANOYL ANILIDES                                                  __________________________________________________________________________     ##STR23##                                                                    Example                                                                            R.sup.1                                                                            R.sup.2                                                                             R.sup.3                                                                            R.sup.4                                                                              R.sup.5 Reactants                                 __________________________________________________________________________    67   CH.sub.3                                                                           H     CH.sub.3                                                                           H      CH.sub.3 CO                                                                           2-(o-methylaminophenethyl)-1-methylpip                                        eridine                                                                       and acetic anhydride                      68   n-C.sub.4 H.sub.9                                                                  H     CH.sub.3                                                                           H      CH.sub.3 CO                                                                           2-(2-n-butylaminophenethyl)-1-methylpi                                        peridine                                                                      and acetic anhydride                      69   H    CH.sub.3 O                                                                          CH.sub.3                                                                           H      CH.sub.3 CO                                                                           2-(2-amino-5-methoxyphenethyl)-1-methy                                        l-                                                                            piperidine and acetic anhydride           70   H    H     n-C.sub.4 H.sub.9                                                                  H      CH.sub.3 CO                                                                           2-(o-aminophenethyl)-1-n-butylpiperidi                                        ne and                                                                        acetic anhydride                          71   H    H     CH.sub.3                                                                           C.sub.2 H.sub.5                                                                      CH.sub.3 CO                                                                           2-(o-aminophenethyl)-5-ethyl-1-methyl-                                        piperidine and acetic anhydride           72   H    H     CH.sub.3                                                                           CON(C.sub.2 H.sub.5).sub.2                                                           CH.sub.3 CO                                                                           6-(o-aminophenethyl)-N,N-diethyl-1-met                                        hyl-                                                                          piperidine-3-carboxamide and acetic                                           anhydride                                 73   H    H     CH.sub.3                                                                           H      CH.sub.3 (CH.sub.2).sub.2 CO                                                          2-(o-aminophenethyl)-1-methylpiperidin                                        e and                                                                         n-butyric anhydride                       74   H    H     CH.sub.3                                                                           H      (CH.sub.3).sub.2 CHCO                                                                 2-(o-aminophenethyl)-1-methylpiperidin                                        e and                                                                         iso-butyric anhydride                     75   H    n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                           H      CH.sub.3 CH.sub.2 CO                                                                  2-(2-amino-5-n-butoxphenethyl)-1-methy                                        l-                                                                            piperidine and propionic                  __________________________________________________________________________                                        anhydride                             

Reduction of alkanoyl anilides with lithium aluminum hydride provides2-(o-alkylaminophenethyl)-1-alkylpiperidine intermediates which can beacylated or sulfonylated to provide additional products of the presentinvention. For example, reduction of alkanoyl anilides of Table IVwherein R¹ is hydrogen according to the method of Example 2 (e) withlithium aluminum hydride provides

2-(2-ethylamino-5-methoxyphenethyl)-1-methylpiperidine,

2-(o-ethylaminophenethyl)-1-n-butylpiperidine,

2-(o-ethylaminophenethyl)-5-ethyl-1-methylpiperidine,

2-(2-n-butylaminophenethyl)-1-methylpiperidine,

2-(o-isobutylaminophenethyl)-1-methylpiperidine,

2-(2-n-propylamino-5-n-butoxyphenethyl)-1-methylpiperidine.

EXAMPLE 76 2'-[2-(1-Methyl-2-piperidyl)ethyl]-methanesulfonanilide

Reaction of methanesulfonyl chloride (5.7 g., 0.05 mole) with2-(o-aminophenethyl)-1-methylpiperidine (9.8 g., 0.045 mole) in 75 ml.of pyridine according to the procedure of Example 25 provides 5.6 g.(41%) of analytically pure2'-[2-(1-methyl-2-piperidyl)ethyl]methanesulfonanilide (crystallizedfrom ethanol), m.p. 91.5°-93.5° C. (corr.).

Analysis. Calcd. for C₁₅ H₂₄ N₂ O₂ S: C, 60.78; H, 8.16; N, 9.45. Found:C, 60.55; H, 8.12; N, 9.54.

EXAMPLES 77-86 Additional alkanesulfonanilides

The alkanesulfonanilides listed in Table V are prepared from thespecified reactants according to the procedures of Examples 25-32 aswill be clear to those skilled in the art.

                                      TABLE V                                     __________________________________________________________________________    ADDITIONAL ALKANESULFONANILIDES                                               __________________________________________________________________________     ##STR24##                                                                    Example                                                                            R.sup.1                                                                            R.sup.2                                                                             R.sup.3                                                                            R.sup.4                                                                              R.sup.5 Reactants                                 __________________________________________________________________________    77   CH.sub.3                                                                           H     CH.sub.3                                                                           H      CH.sub.3 SO.sub.2                                                                     2-(o-methylaminophenethyl)-1-methylpip                                        eridine                                                                       and methanesulfonyl chloride              78   n-C.sub.4 H.sub.9                                                                  H     CH.sub.3                                                                           H      CH.sub.3 SO.sub.2                                                                     2-(2-n-butylaminophenethyl)-1-methylpi                                        peridine                                                                      and methanesulfonyl chloride              79   H    CH.sub.3 O                                                                          CH.sub.3                                                                           H      CH.sub.3 SO.sub.2                                                                     2-(2-amino-5-methoxyphenethyl)-1-methy                                        l-                                                                            piperidine and methanesulfonyl                                                chloride                                  80   H    H     n-C.sub.4 H.sub.9                                                                  H      CH.sub.3 SO.sub.2                                                                     2-(o-aminophenethyl)-1-n-butylpiperidi                                        ne and                                                                        methanesulfonyl chloride                  81   H    H     CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.3 SO.sub.2                                                                     2-(o-aminophenethyl)-5-methyl-1-methyl                                        -                                                                             piperidine and methanesulfonyl                                                chloride                                  82   H    H     CH.sub.3                                                                           C.sub.2 H.sub.5                                                                      CH.sub.3 SO.sub.2                                                                     2-(o-aminophenethyl)-5-ethyl-1-methyl-                                        piperidine and methanesulfonyl                                                chloride                                  83   H    H     CH.sub.3                                                                           H      CH.sub.3 (CH.sub.2).sub.2 SO.sub.2                                                    2-(o-aminophenethyl)-1-methylpiperidin                                        e                                                                             and n-butanesulfonyl chloride             84   H    H     CH.sub.3                                                                           H      (CH.sub.3).sub.2 CHSO.sub.2                                                           2-(o-aminophenethyl)-1-methylpiperidin                                        e                                                                             and isopropanesulfonyl chloride           85   H    n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                           H      CH.sub.3 (CH.sub.2).sub.2 SO.sub.2                                                    2-(2-amino-5-n-butoxyphenethyl)-1-meth                                        yl-                                                                           piperidine and n-propanesulfonyl                                              chloride                                  86   H    H     CH.sub.3                                                                           CON(C.sub.2 H.sub.5).sub.2                                                           CH.sub.3 SO.sub.2                                                                     6-(o-aminophenethyl)-N,N-diethyl-1-met                                        hyl-                                                                          piperidine-3-carboxamide and                                                  methane-                                                                      sulfonyl chloride                         __________________________________________________________________________

EXAMPLE 87 4-Amino-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide

Reaction of 4-nitrobenzoyl chloride (6.5 g., 0.035 mole) and2-(o-aminophenethyl)-1-methylpiperidine (6.0 g., 0.0275 mole) in 35 ml.of pyridine according to the method of Example 25 provides2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide. Crystallizationfrom ethyl acetate provides analytically pure material, m.p. 162°-163.5°C.

Analysis. Calcd. for C₂₁ H₂₅ N₃ O₃ : C, 68.64; H, 6.86; N, 11.44. Found:C, 68.58; H, 6.84; N, 11.30.

Reduction of 2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide (6.5g., 0.018 mole) in 100 ml. of ethanol employing 2 g. of palladium oncarbon catalyst (10%) according to Example 2 (a) affords4-amino-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Crystallizationof the product from acetonitrile provides the analytically puresubstance, m.p. 147°-148.5° C. (corr.).

Analysis. Calcd. for C₂₁ H₂₇ N₃ O: C, 74.74; H, 8.07; N, 12.45. Found:C, 74.75; H, 8.06; N, 12.47.

EXAMPLE 88 4-Acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide

Reaction of 2-(o-aminophenethyl)-1-methylpiperidine withp-acetoxybenzoyl chloride in pyridine according to Example 1 provides4-acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Analyticallypure product is obtained by crystallization from isopropyl ether, m.p.88°-108° C. (corr.). The broad melting point of the analytically purematerial is due to polymorphism.

Analysis. Calcd. for C₂₃ H₂₈ N₂ O₃ : C, 72.60; H, 7.42; N, 7.36. Found:C, 72.79; H, 7.38; N, 7.31.

EXAMPLE 89 4-Hydroxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide

4'-Acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide suspended in1N sodium hydroxide is stirred until solution takes place. The pH of theaqueous solution is adjusted to 9 with 6N hydrochloric acid and an oilprecipitates which is extracted with ethyl acetate. The product isolatedby removal of the ethyl acetate solvent is crystallized from ethanol toprovide analytically pure4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p.178.5°-182.5° C. (corr.).

Analysis. Calcd. for C₂₁ H₂₆ N₂ O₂ : C, 74.52; H, 7.74; N, 8.28. Found:C, 74.59; H, 7.47; N, 8.31.

EXAMPLES 90-111 Additional benzanilides

The benzanilides listed in Table VI and Table VII are prepared accordingto the procedures of Examples 25-32 and 87-89 as will be clear to thoseskilled in the art.

                                      TABLE VI                                    __________________________________________________________________________    ADDITIONAL BENZANILIDES                                                       __________________________________________________________________________     ##STR25##                                                                    Example                                                                            R.sup.1                                                                            R.sup.2                                                                             R.sup.3                                                                            R.sup.4                                                                              Ar         Reactants                              __________________________________________________________________________    90   CH.sub.3                                                                           H     CH.sub.3                                                                           H      C.sub.6 H.sub.5                                                                          2-(o-methylaminophenethyl)-1-methyl                                           -                                                                             piperidine and benzoyl chloride        91   n-C.sub.4 H.sub.9                                                                  H     CH.sub.3                                                                           H      C.sub.6 H.sub.5                                                                          2-(2-n-butylaminophenethyl)-1-methy                                           l-                                                                            piperidine and benzoyl chloride        92   H    CH.sub.3 O                                                                          CH.sub.3                                                                           H      C.sub.6 H.sub.5                                                                          2-(2-amino-5-methoxyphenethyl)-1-                                             methylpiperidine and benzoyl                                                  chloride                               93   H    n-C.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                           H      C.sub.6 H.sub.5                                                                          2-(2-amino-5-n-butoxyphenethyl)-1-                                            methylpiperidine and benzoyl                                                  chloride                               94   H    H     n-C.sub.4 H.sub.9                                                                  H      C.sub.6 H.sub.5                                                                          2-(o-aminophenethyl)-1-n-butylpiper                                           idine                                                                         and benzoyl chloride                   95   H    H     CH.sub.3                                                                           CH.sub.3                                                                             C.sub. 6 H.sub.5                                                                         2-(o-aminophenethyl)-5-methyl-1-met                                           hyl j -      piperidine and                                                   benzoyl chloride                       96   H    H     CH.sub.3                                                                           n-C.sub.4 H.sub.9                                                                    C.sub.6 H.sub.5                                                                          2-(o-aminophenethyl)-5-n-butyl-1-                                             methylpiperidine and benzoyl                                                  chloride                               97   H    H     CH.sub.3                                                                           H      p-n-C.sub.4 H.sub.9SC.sub.6 H.sub.5                                                      2-(o-aminophenethyl)-1-methylpiperi                                           dine                                                                          and p-n-butylthiobenzoyl chloride      98   H    H     CH.sub.3                                                                           H      m-C.sub.4 H.sub.9OC.sub.6 H.sub.4                                                        2-(o-aminophenethyl)-1-methylpiperi                                           dine                                                                          and m-n-butoxybenzoyl chloride         99   H    H     CH.sub.3                                                                           H                                                                                     ##STR26## 2-(o-aminophenethyl)-1-methylpiperi                                           dine and 3,5-diisopropoxybenzoyl                                              chloride                               100  H    H     CH.sub.3                                                                           H                                                                                     ##STR27## 2-(o-aminophenethyl)-1-methylpiperi                                           dine and 3,4,5-tri-n-butoxybenzoyl                                            chloride                               101  H    H     CH.sub.3                                                                           H      p-FC.sub.6 H.sub.4                                                                       2-(o-aminophenethyl)-1-methylpiperi                                           dine                                                                          and 4-fluorobenzoyl chloride           102  H    H     CH.sub.3                                                                           CON(C.sub.2 H.sub.5).sub.2                                                           C.sub.6 H.sub. 5                                                                         6-(o-aminophenethyl)-N,N-diethyl-1-                                           methylpiperidine-3-carboxamide                                                and                                                                           benzoyl chloride                       103  H    CH.sub.3 O                                                                          CH.sub.3                                                                           H      p-NH.sub.2 C.sub.6 H.sub.4                                                               2-(2-amino-5-methoxyphenethyl)-1-me                                           thyl-                                                                         piperidine and p-nitrobenzoyl                                                 chloride                               __________________________________________________________________________

                                      TABLE VII                                   __________________________________________________________________________    ADDITIONAL BENZANILIDES                                                       __________________________________________________________________________     ##STR28##                                                                    Example                                                                            Chemical Name        Ar       M.P. ° C.                                                                       Calcd.                                                                              Found                       __________________________________________________________________________    104  2'-[2-(1-methyl-1-piperidyl)ethyl]- benzanilide                                                     ##STR29##                                                                             85.5 - 87                                                                               ##STR30##                                                                          C 78.41 H  8.13 N  8.68     105  4-chloro-2'-[2-(1-methyl-2-piperidyl)- ethyl]benzanilide                                            ##STR31##                                                                             130 - 131                                                                               ##STR32##                                                                          C 70.84 H  7.05 N  7.84     106  4-(methylthio)-2'-[2-(1-methyl-2- piperidyl)ethyl]benzanilide                                       ##STR33##                                                                             145 - 145.5                                                                             ##STR34##                                                                          C 71.86 H  7.59 N  7.54     107  4-methoxy-2'-[2-(1-methyl-2- piperidyl)ethyl]benzanilide                                            ##STR35##                                                                             131.5 - 132.5                                                                           ##STR36##                                                                          C 74.91 H  7.83 N  7.90     108  3-methoxy-2'-[2-(1-methyl-2- piperidyl)ethyl] benzanilide                                           ##STR37##                                                                             124.5 - 126.5                                                                           ##STR38##                                                                          C 75.16 H  7.94 N  7.88     109  3,4-dimethoyx-2'-[2-(1-methyl-2- piperidyl)ethyl]benzanilide                                        ##STR39##                                                                             123 - 124.5                                                                             ##STR40##                                                                          C 72.12 H  7.88 N  7.39     110                                                                                 ##STR41##                                                                                          ##STR42##                                                                             140.5 - 142                                                                            C 65.04 H  6.87 N                                                                   C 65.00 H  6.93 N  5.65     111                                                                                 ##STR43##                                                                                          ##STR44##                                                                             115 - 122                                                                              C 60.54 H  7.34 N                                                                   C 60.33 H  7.21 N           __________________________________________________________________________                                                      5.18                    

EXAMPLE 112 Pharmaceutical Compositions

The substituted piperidines characterized by Formula I are compoundedwith pharmacologically acceptable carriers to provide compositionsuseful in the present invention. Typical of the pharmaceuticalcompositions are the following:

A. Tablets

The piperidines of Formula I are compounded into tablets according tothe following example.

    ______________________________________                                        Material                  Amount                                              ______________________________________                                        4-Methoxy-2'-[2-(1-methyl-2-piperidyl)-                                        ethyl]benzanilide        50.0     g.                                         Magnesium stearate        1.3      g.                                         Corn starch               12.4     g.                                         Corn starch pregelatinized                                                                              1.3      g.                                         Lactose                   185.0    g.                                         ______________________________________                                    

The foregoing materials are blended in a twin-shell blender and thengranulated and pressed into tablets weighing 250 mg. each. Each tabletcontains 50 milligrams of active ingredient. The tablet may be scored inquarters so that a dose 12.5 mg. of active ingredient may beconveniently obtained.

B. CAPSULES

The piperidines of Formula I are compounded into capsules according tothe following example.

    ______________________________________                                               Materials     Amount                                                   ______________________________________                                        Active ingredient    125 mg.                                                  Lactose              146.0 mg.                                                Magnesium stearate    4.0 mg.                                                 ______________________________________                                    

The foregoing materials are blended in a twin-shell blender and thenfilled into No. 1 hard gelatin capsules. Each capsule contains 125 mg.of active ingredient.

C. SOLUTION FOR INTRAVENOUS ADMINISTRATION

The substituted piperidines characterized by Formula I are formulatedfor parenteral administration according to the following example. Asterile solution suitable for intravenous injection is prepared bydissolving 10.0 g. of4-methoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide in a minimalamount of 0.5 N hydrochloric acid. This solution is adjusted to a pH of4.3 with 0.1 N sodium hydroxide and diluted to 1000 ml. total volumewith saline. The solution is sterilized by passage through abacteriological filter and aseptically filled into 10 ml. sterileampoules. Each milliliter of solution contains 10 mg. of the activeingredient, 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide.

EXAMPLE 113 4-(t-Butoxy)-2'-[2-(1-methyl-2-piperidyl)ethyl] benzanilide

A mixture of 2-(o-aminophenethyl)piperidine (38.8 g., 0.178 mole),methyl 4-(t-butoxy)benzoate (36.9 g., 0.178 mole), sodium methoxide(10.6 g., 0.195 mole) and 600 ml. of benzene is heated to reflux in aflask fitted with a 30 cm vacuum-jacketed fractionating column packedwith Rashig rings, and a variable takeoff head. The methanol-benzeneazeotrope is removed at intervals until no more forms. After cooling to25° C., the mixture is washed (H₂ O, sat. brine), dried (MgSO₄), andevaporated. Crystallization of the residue thus obtained from heptaneyields 15.2 g. (21%) of4-(t-butoxy)-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p.91°-93.5° C. (corr.).

Analysis. Calcd. for C₂₅ H₃₄ N₂ O₂ : C, 76.10; H, 8.69; N, 7.10. Found:C, 76.06; H, 8.59; N, 7.10.

EXAMPLE 114 2'-[2-(1-Methyl-2-piperidyl)ethyl]-p-toluanilide

Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (80 g., 0.036 mole)with p-toluoyl chloride (6.2 g., 0.04 mole) in 50 ml. of pyridineaccording to the method of Example 25 provides2'-[2-(1-methyl-2-piperidyl)ethyl]-p-toluanilide. Crystallization fromisopropyl ether and then from isopropyl alcohol provides 3.9 g., (32%)of analytically pure material, m.p. 90.5°-92° C. (corr.).

Analysis. Calcd. for C₂₂ H₂₈ N₂ O: C, 78.53; H, 8.39; N, 8.33. Found: C,78.56; H, 8.09; N, 8.05.

EXAMPLE 115 2'-[2-(1-Methyl-2-piperidyl)ethyl]picolinanilide

A solution of 2-(o-aminophenethyl)-1-methylpiperidine (8.0 g., 0.037mole) and ethyl picolinate (5.5 g., 0.037 mole) in DMSO (20 ml.) istreated with NaH (57%) in oil (1.6 g., 0.037 mole) with intermittentcooling to moderate the resulting vigorous reaction. After 2 hr., themixture is poured into 150 ml. of H₂ O and the product isolatedaccording to the procedure of Example 25. Crystallizations fromisopropyl ether affords 5.9 (50%) of analytically pure2'-[2-(1-methyl-2-piperidyl)-ethyl]picolinanilide, m.p. 65.5°-67° C.(corr.).

Analysis. Calcd. for C₂₀ H₂₅ N₃ O: C, 74.27; H, 7.79; N, 12.99. Found:C, 74.33; H, 7.92; N, 12.99.

EXAMPLE 116 2-[2-[2-(1-Methyl-2-piperidyl)ethyl]phenylcarbamoyl]benzoicacid

To a solution of 2-(o-aminophenethyl)-1-methylpiperidine (8.73 g., 0.04mole) in 100 ml. of EtOAc is rapidly added a solution of phthalicanhydride (5.93 g., 0.04 mole) in 100 ml. of EtOAc. Solid productseparates after a short time and is collected and crystallized from CH₃CN, yielding 7.2 g. (49%) of2-[2-[2-(1-methyl-2-piperidyl)ethyl]phenylcarbamoyl]benzoic acid, m.p.171°-172° C. (corr.).

Analysis. Calcd. for C₂₂ H₂₆ N₂ O₃ : C, 72.10; H, 7.15; N, 7.65. Found:C, 72.22; H, 7.10; N, 7.81.

EXAMPLE 117 2'-[2-(1-Methyl-2-piperidyl)ethyl]isonipecotincanilide

2'-[2-(1-Methyl-2-piperidyl)ethyl]isonicotinanilide hydrate (9.7 g.,0.028 mole) is hydrogenated on a Parr apparatus in glacial acetic acid(200 ml.) using 10% Pd/C (4.0 g.) as the catalyst. Evaporation of theAcOH followed by a basic workup according to the procedure of Example 25affords the crude product which crystallized from EtOAc yields 4.3 g.(46%) of 2'-[2-(1-methyl-2-piperidyl)ethyl]isonipecoticanilide, m.p.157°-159° C. (corr.).

Analysis. Calcd. for C₂₀ H₃₁ N₃ O: C, 72.90; H, 9.48; N, 12.76. Found:C, 73.30; H, 9.46; N, 12.76.

Example 118 4-Methoxy-2'-[2-(1-methyl-2-piperidyl)propyl]-benzanilide

a. 2-(β-Methyl-2-nitrostyryl)pyridine

A mixture of o-nitrobenzaldehyde (127 g., 0.84 mole), 2-ethylpyridine(90 g., 0.84 mole) and acetic anhydride (171 g., 1.68 mole) is heated atreflux for 24 hr. Excess acetic anhydride is evaporated in vacuo and theresidue poured into 500 ml. of water. The mixture is adjusted to pH 11with 50% NaOH providing a precipitate which is collected and dried.Crystallization from isopropyl ether yields 136.7 g. (67%) of2(-β-methyl-2-nitrostyryl)-pyridine, m.p. 62° -64° C. which, after asecond crystallization, is analytically pure.

Analysis. Calcd. for C₁₄ H₁₂ N₂ O₂ : C, 69.99; H, 5.03; N, 11.66. FoundC, 70.38; H, 5.07; N, 11.70.

b. 2-[2-(2-Aminophenyl)-1-methylethyl]pyridine

2-(β-Methyl-2-nitrostyryl)pyridine (24.0 g., 0.1 mole) is hydrogenatedon a Parr apparatus in 200 ml. of ethanol with 3 g. of 10% Pd/C ascatalyst. The catalyst is filtered and the filtrate evaporated,providing 2-[2-(2-aminophenyl)-1-methylethyl]pyridine.

c. 2-[2-(2-Formamidophenyl)-1-methylethyl]pyridine.

Reaction of 2-[2-(2-aminophenyl)-1-methylethyl]pyridine (21 g., 0.1mole) with 42 ml. of acetic-formic anhydride, according to the procedureof Example 2(b), affords2-[2-(2-formamidophenyl)-1-methylethyl]-1-methylpyridinium iodide.

d. 2-[2-(2-Formamidophenyl)-1-methylethyl]-1-methylpyridinium iodide

Reaction of 2-[2-(2-formamidophenyl)-1-methylethyl]pyridine (24 g., 0.1mole) with methyl iodide (28.4 g., 0.2 mole) according to the procedureof Example 2(c), affords 29.5 g. (77%) of2-[2-(2-formamidophenyl-1-methylethyl]-1-methylpyridinium iodide, m.p.184° - 188° C.

Analysis. Calcd. for C₁₆ H₁₉ IN₂ O: C, 50.28; H, 5.01; N, 7.33. Found:C, 50.46; H, 5.01; N, 7.20.

e. 2-[2-(2-Aminophenyl)-1-methylethyl]-1-methylpiperidine

2-[2-(2-Formamidophenyl)-1-methylethyl]-1-methylpyridinium iodide (25.4g., 0.0665 mole) is hydrogenated in a Parr apparatus in 200 ml. ofethanol with Pt₂ O (0.6 g.) as catalyst. A basic workup gave2-[2-(2-formamidophenethyl)-1-methylethyl]-1-methylpiperidine which isdissolved in 200 ml. of methanol, mixed with 45 ml. of concentratedhydrochloric acid, permitted to stand for 24 hr. and then heated atreflux for 4 hr. A basic workup and distillation yields2-[2-(2-aminophenyl)-1-methylethyl]-1-methylpiperidine, n_(D) ²⁵.sup.°,1.5520, b.p. 121° - 124° C./0.1 Torr.

Analysis. Calcd. for C₁₅ H₂₄ N₂ : C, 77.53; H, 10.41; N, 12.06. Found:C, 77.26; H, 10.46; N, 12.07.

f. 4-Methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)ethyl]benzanilide

Reaction of 2-[2-(2-aminophenyl)-1-methylethyl]-1-methylpiperidine withanisoyl chloride, according to the procedure of Example 25, provides4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)-ethyl]benzanilide as a72:28 mixture of diastereoisomers (according to nmr), m.p. 125.5° -136.5° C. (corr.).

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₂ : C, 75.37; H, 8.25; N, 7.64. Found:C, 75.24; H, 8.42; N, 7.34.

The diastereoisomeric mixture of4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)ethyl]benzanilide (42 g.)is fractionally recrystallized from ethyl acetate following a triangularscheme according to the technique of A. Weissberger and E. S. Proshauer,"Technique of Organic Chemistry" Vol. III, 490, Interscience Publishers,Inc., New York, 1955 as follows:

    ______________________________________                                                                     A:B Ratio of Racemates                           Crop   Wt.g.    M.P. (° C.)                                                                         by nmr                                           ______________________________________                                        1     15.3      117-121      --                                               1A    11.4      123-135      72:28                                            1B    4.9       136-143      --                                               1C    2.9       143-146      95:5                                             2     27.1      106-116      --                                               2A    4.65      116-120      52:48                                            2B    3.0       121-124      58:42                                            2C    2.35      139-142      80:20                                            3     9.35      105-111      24:76                                            4     6.65      100-110      20:80                                            ______________________________________                                    

Crops 1C and 2C are combined and recrystallized to give 3.5 g. RacemateA, 4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)-ethyl]benzanilideisomer (less than 5% Racemate B isomer), m.p. 146° - 147.5° C. (corr.),δ, 2.1 (S, N-CH₃, 3H).

Crop 4 is recrystallized from isopropyl ether to provide 3.45 g. ofRacemate B,4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)-ethyl]benzanilide isomer(less than 5% Racemate A isomer), m.p. 96.0° - 97.5° C. (corr.), δ, 2.25(S, N-CH₃, 3H).

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₂ : C, 75.37; H, 8.25; N, 7.64. Found:(Racemate A) C, 75.26; H, 8.24; N, 7.50; (Racemate B) C, 75.06; H, 8.32;N, 7.50.

EXAMPLE 119 2'-[2-(1-Ethyl-2-piperidyl)ethyl]-p-anisanilide

a. 1-Ethyl-2-(o-formamidophenethyl)pyridinium iodide

A solution of 2-(o-formamidophenethyl)pyridine (36.1 g., 0.159 mole) andiodoethane (30.0 g., 0.191 mole) in CH₃ CN (450 ml.) heated at refluxfor 18 hr., cooled and diluted to incipient turbidity provides1-ethyl-2-(o-formamidophenethyl)pyridinium iodide, yield 44.8 g. (74%),m.p. 155° - 157° C.

b. 1-Ethyl-2-(2-formamidophenethyl)piperidine

To a solution of 1-ethyl-2-(o-formamidophenethyl)pyridinium iodide (44.8g., 0.117 mole), 50% NaOH (11.2 g., 0.14 mole), and water (40 ml.) inmethanol (330 ml.) is added portionwise NaBH₄ (5.32 g., 0.14 mole). Thesolution is stirred for 2 hr. and evaporated. Water is added to theresidue thus obtained and the mixture extracted with ether. The etherealextracts are dried (MgSO₄ ) and evaporated. The residue taken up in 200ml. of ethanol and hydrogenated in a Parr apparatus using 5 g. of 10%palladium on carbon as catalyst affords1-ethyl-2-(2-formamidophenethyl)piperidine.

c. 2-(2-Aminophenethyl)-1-ethylpiperidine

A solution of 1-ethyl-2-(2-formamidophenethyl)piperidine (27.6 g., 0.11mole), methanol (450 ml.) and concentrated HCl (100 ml.) allowed tostand for 24 hr. provides 2-(2-aminophenethyl)-1-ethylpiperidine,purified by distillation, yield 17.72 g. (69%), b.p. 107° - 128° C./0.1Torr, n_(D) ³⁰.sup.° 1.5510.

Analysis. Calcd. for C₁₅ H₂₄ N₂ : C, 77.53; H, 10.41; N, 12.06. Found:C, 77.29; H, 10.54; N, 11.87.

d. 2'-[2-(1-Ethyl-2-piperidyl)ethyl]-p-anisanilide.

Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with anisoyl chlorideaccording to the procedure of Example 25 provides2'-[2-(1-ethyl-2-piperidyl)ethyl]-p-anisanilide, m.p. 136.5° -137.5° C.(corr.), from ethyl acetate.

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₂ : C, 75.37; H, 8.25; N, 7.64. Found:C, 75.25; H, 8.30; N, 7.45.

Example 120 4-Bromo-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide

Reaction of 4-bromobenzoyl chloride with2-(o-aminophenethyl)-1-methylpiperidine according to the procedure ofExample 114 affords4-bromo-2'-[2-(1methyl-2-piperidyl)ethyl]benzanilide, m.p. 137.5° -138.5° C. (corr.), from ethyl acetate.

Analysis. Calcd. for C₂₁ H₂₅ BrN₂ O: C, 62.83; H, 6.28; N, 6.98. Found:C, 62.55; H, 6.27; N, 6.92.

EXAMPLE 121 4-Fluoro-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide

Reaction of 2-(o-aminophenethyl)piperidine with 4-fluorobenzoyl chlorideaccording to the procedure of Example 114 affords4-fluoro-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 115.5° -116.5° C. (corr.), from isopropyl ether.

Analysis. Calcd. for C₂₁ H₂₅ FN₂ O: C, 74.10; H, 7.41; N, 8.23. Found:C, 74.18; H, 7.35; N, 8.26.

Example 1222'-[2-(1-Methyl-2-piperidyl)ethyl]-4-(trifluoromethyl)benzanilide

Reaction of 2-(o-aminophenethyl)piperidine with4-(trifluoromethyl)benzoyl chloride according to the procedure ofExample 114 affords2'-[2-(1-methyl-2-piperidyl)ethyl]-4-(trifluoromethyl)benzanilide, m.p.149.5° - 150.0° C. (corr.), from isopropyl ether.

Analysis. Calcd. for C₂₂ H₂₅ F₃ N₂ O: C, 67.88; H, 6.46; N, 7.18. Found:C, 67.68; H, 6.39; N, 7.12.

Example 123 4-(t-Butyl)-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilidehemimucate hemiethanolate

Reaction of 2-(o-aminophenethyl)-piperidine with 4-(t-butyl)benzoylchloride according to the procedure of Example 114 affords4-(t-butyl)-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide hemimucatehemiethanolate, m.p. 101° - 120.5° C. (corr.) bubbles, from absoluteethanol.

Analysis. Calcd. for C₂₅ H₃₄ N₂₀ O.1/2 C₆ H₁₀ O₈ .1/2C₂ H₅ OH: C, 68.75;H, 8.36; N, 5.53. Found: C, 68.43; H, 8.32; N, 5.41.

EXAMPLE 124 4-Dimethylamino-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide

Reaction of ethyl 4-dimethylaminobenzolate with2-(o-aminophenethyl)-1-methylpiperidine according to the procedure ofExample 115 provides 4-dimethylamino-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 115° - 116.5° C. (corr.), from isopropyl ether-ethylacetate.

Analysis. Calcd. for C₂₃ H₃₁ N₃ O: C, 75.58; H, 8.55; N, 11.50. Found:C, 75.94; H, 8.63; N, 11.52.

EXAMPLE 125 2'-[2-(1-Methyl-2-piperidyl)ethyl]-3-furancarboxanilide

Reaction of ethyl furan-3-carboxylate prepared by the method of Boyd etal, Synthesis, 545, (Oct. 1971) with2-(2-amino-phenethyl)-1-methylpiperidine according to the procedure ofExample 115 provides2'-[2-(1-methyl-2-piperidyl)ethyl]-3-furancarboxanilide, m.p. 114.5° -115.5° C. (corr.), from isopropyl ether and then ethyl acetate.

Analysis. Calcd. for C₁₉ H₂₄ N₂ O₂ : C, 73.04; H, 7.74; N, 8.97. Found:C, 73.30; H, 7.58; N, 9.02.

EXAMPLE 126 2'-[2-(1methyl-2-piperidyl)ethyl]isonicotinanilide hydrate

Reaction of 2-(o-aminophenethyl)piperidine with ethyl isonicotinateaccording to the procedure of Example 115 affords2'-[2-(1-methyl-2-piperidyl)ethyl]isonicotinanilide hydrate, m.p. 93° -100.5° C. (corr.), from ethyl acetate saturated with water.

Analysis. Calcd. for C₂₀ H₂₅ N₃ O.H₂ O: C, 70.35; H, 7.97; N, 12.31.Found: C, 70.64; H, 7.82; N, 12.25.

EXAMPLE 127 2'-[2-(1-Methyl-2-piperidyl)ethyl]nicotinanilide

Reaction of 2-(o-aminophenethyl)piperidine with ethyl nicotinateaccording to the procedure of Example 115 affords2'-[2-(1-methyl-2-piperidyl)ethyl]nicotinanilide, m.p. 88° - 90° C.(corr.), from isopropyl ether.

Analysis. Calcd. for C₂₀ H₂₅ N₃ O: C, 74.27; H, 7.79; N, 12.99. Found:C, 74.32; H, 7.76; N, 12.97.

EXAMPLE 128 2'-[2-(1-Ethyl-2-piperidyl)ethyl]cinnamanilide

Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with cinnamoylchloride according to the procedure of Example 25 provides2'-[2-(1-ethyl-2-piperidyl)ethyl]cinnamanilide, m.p. 119.5° - 121.5° C.(corr.), from ethyl acetate and then acetonitrile.

Analysis. Calcd. for C₂₄ H₃₀ N₂ O: C, 79.51; H, 8.34; N, 7.73. Found: C,79.49; H, 8.44; N, 7.57.

EXAMPLE 129 2'-[2-(1-Methyl-2-piperidyl)ethyl]phenylpropiolanilide

Reaction of ethyl propiolate with2-(o-aminophenethyl)-1-methylpiperidine according to the procedure ofExample 115 affords2'-[2-(1-methyl-2-piperidyl)ethyl]phenylpropiolanilide, m.p. 104.5° -106.5° C. (corr.), from ethyl acetate.

Analysis. Calcd. for C₂₃ H₂₆ N₂ O: C, 79.73; H, 7.56; N, 8.09. Found: C,79.62; H, 7.63; N, 8.15.

EXAMPLE 130 2'-[3-(1-Methyl-2piperidyl)propyl]cinnamanilide

A solution of 4-methoxy-2'-[3-(1-methyl-2-piperidyl)propyl]-benzanilide(3.5 g., 0.0095 mole) and concentrated HCl (50 ml.) is heated at refluxfor 16 hr., diluted with H₂ 0 (100 ml.), basified with 50% NaOH, andextracted with Et₂ O. The Et₂ O extracts are combined, washed (H₂ O andsaturated NaCl), dried over MgSO₄, and concentrated to give 2.2 g. of2-(o-aminophenylpropyl)-1-methylpiperidine. The amine is dissolved inpyridine (50 ml.) and a solution of cinnamoyl chloride (1.8 g., 0.011mole) in THF (10 ml.) added. The reaction mixture is stirred for 3 hr.,then concentrated to dryness. The residue is dissolved in water,basified with 50% NaOH, and extracted with EtOAc. The EtOAc extracts arewashed (H₂ O + saturated NaCl), dried over magnesium sulfate, andconcentrated to give 3.4 g. of oil which is chromatographed on silica ARCC-7 (Mallinckrodt). Elution first with CHCl₃ to remove impurities, thenwith EtOAc to remove the product and concentration of the EtOAc eluategave 2.3 g. of solid which crystallized from EtOAc yields 1.6 g. (46%)of 2'-[3 -(1 -methyl-2-piperidyl)propyl ]cinnamanilide, m.p. 130° - 132°C. Further crystallization from ethyl acetate-isopropyl ether providesanalytically pure product, m.p. 133.5° - 134.5° C.

Analysis. Calcd. for C₂₄ H₃₀ N₂ O: C, 79.51; H, 8.34; N, 7.73. Found: C,79.81; H, 8.50; N, 7.55.

EXAMPLE 131 4-Methoxy-4',5'-methylenedioxy-2'-[2-(1-methyl-2-piperidyl)ethyl]dbenzanilide

a. 2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine

A mixture of 6-nitropiperonal (95 g., 0.487 mole), 2-picoline (45.3 g.,0.487 mole) and acetic anhydride (99.5 g., 0.974 mole) is heated underreflux for 24 hr. The resulting solution is poured into water and theprecipitate which forms is collected. Crystallization from EtOAc affords65.9 g. (51%) of 2-(4,5-methylenedioxy-2-nitrostyryl)pyridine, m.p. 167°-170° C.

Analysis. Calcd. for C₁₄ H₁₀ N₂ O₄ : C, 62.22; H, 3.73; N, 10.37. Found:C, 62.34; H, 3.46; N, 10.17.

b. 4-methoxy-4', 5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]-benzanilide

2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) ishydrogenated on a Parr apparatus in 200 ml. of ethanol with 2.0 g. of10% palladium on carbon as catalyst. After the reduction is complete,the mixture is filtered and the solvent evaporated. The residueconsisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine isimmediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5g., 0.044 mole) added. The solution is stirred for 30 min. A basicworkup according to the procedure of Example 25 affords 10 g. of4-methoxy-4', 5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilideobtained analytically pure by crystallization from ethyl acetate.

Analysis. Calcd. for C₂₂ H₂₀ N₂ O₄ : C, 70.20; H, 5.36; N, 7.44. Found:C, 70.20; H, 5.45; N, 7.40.

c. 4-Methoxy-4',5'-methylenedioxy-2'-[2-(1methyl-2-pyridinium)-ethyl]benzanilidemethylsulfate

To a solution of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide in acetone (200ml.) is added dimethyl sulfate (3.32 g., 0.0264 mole). After 18 hr. atreflux, the mixture is cooled, 4-methoxy-4',5'-methylenedioxy-2'-[2-(1-methyl-2-pyridinium)ethyl]benzanilidemethylsulfate collected and used in the following step without furtherpurification.

d.4-Methoxy-4';5'-methylenedioxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide

Reduction of 4-methoxy-4',5'-methylenedioxy-2'-[2-(1-methyl-2-pyridinium)ethyl]benzanilide methylsulfate (9.6 g., 0.024 mole) in a Parr apparatus in 100 ml. of ethanolusing PtO₂ (0.2 g.) as catalyst according to the procedure of Example 1yields 4-methoxy-4',5'-methylenedioxy-2'-[2-(1-methyl-2-piperidyl]benzanilide, m.p 112° -113° C. (corr.), from methanol-water and then ethyl acetate-isopropylether.

Analysis. Calcd. for C₂₃ H₂₈ N₂ O₄ : C, 69.67; H, 7.12; N, 7.07. Found:C, 69.66; H, 7.33; N, 6.85.

EXAMPLE 132 2'-[(1-Methyl-2-piperidyl)methyl]-p-anisanilide

a. 4Methoxy-2'-[hydroxy(2-pyridyl)methyl]benzanilide

Pyridyl lithium, prepared by adding 2-bromopyridine (30.0 g., 0.19 mole)in 200 ml. of ether to 131 ml. of a hexane solution of 1.6 molar n-butyllithium (0.2 mole) at -70° C., is added in 25 min. to a solution ofo-(4-methoxybenzamido)benzaldehyde (8.9 g., 0.035 mole) in 300 ml. oftetrahydrofuran at -25° C. over a 20 min. period with stirring. Stirringis continued for 20 min. at -25° C. 1 hr. at -10° C. and then at 0° C.for 30 min. The reaction mixture is poured into 1500 ml. of cold 1Nhydrochloric acid, the aqueous layer separated, washed with ethylacetate, made strongly basic with concentrated ammonium hydroxide andextracted with ethyl acetate. The ethyl acetate extract is washed withwater, brine, dried over sodium sulfate and concentrated and the residuethus obtained triturated with ether to provide a 46% yield of4-methoxy-2'-[hydroxy(2-pyridyl)methyl]benzanilide, m.p. 127.5° - 128.5°C. (corr.).

b. 2'(2-Pyridylmethyl)-p-anisanilide.

Treatment of 4-methoxy-2'-[hydroxy(2-pyridyl)methyl]benzanilide withhydrogen iodide according to the procedure of Miller, et al., J. Org.Chem., 24, 1364 (1959 ) provides 2'-(2-pyridylmethyl)-p-anisanilide,m.p. 130.5° - 131.5° C. (corr.), from methanol.

c. 2-[2-(p-Methoxybenzamido)benzyl]pyridinium iodide.

2'-(2-Pyridylmethyl)-p-anisanilide (9.5 g., 0.03 mole) and 0.3 mole ofmethyl iodide in 100 ml. of acetone is refluxed with stirring for aperiod of 64 hr. The reaction mixture filtered and the filter cakewashed with acetone provides a 93% yield of2-[2-(p-methoxybenzamido)-benzyl]-1-methylpyridinium iodide, m.p. 184°-186° C. (corr.).

d. 2'-[(1-Methyl-2-piperidyl)methyl]-p-anisanilide

An ethanol (150 ml.) solution of2-[2(p-methoxybenzamido)benzyl]pyridinium iodide (9.2 g., 0.02 mole)hydrogenated in a Parr apparatus employing 0.2 g. of platinum oxideprovides 2'-[(1-methyl-2-piperidyl)methyl]-p-anisanilide, m.p. 156° -157° C. (corr.), from water-methanol.

Analysis. Calcd. for C₂₁ H₂₆ N₂ O₂ : C, 74.52; H, 7.74; N, 8.28. Found:C, 74.36; H, 7.66; N, 8.29.

Example 133 2'-[1-Methyl-2-piperidyl)ethyl] -p-anisanilide

a. 2'-(2-pyridinecarbonyl)-p-anisanilide

Oxidation of 2'-[ hydroxy(2-pyridyl)methyl] -p-anisanilide with chromicanhydride-pyridine according to the procedure of Ratcliffe, et al., J.Org. Chem., 35, 4000 (1970) provides2'-(2-pyridinecarbonyl)-p-anisanilide, m.p. 132° -133° C. (corr.), fromaqueous isopropanol.

b. 2'-[1-(2-Pyridyl)ethylidene] -p-anisanilide

Methyl lithium (0.24 mole, 142 ml. of 1.7 molar in ether) is added to2'-(2-pyridinecarbonyl)-p-anisanilide (36.6 g., 0.11 mole) in 400 ml. oftetrahydrofuran in 15 min. with stirring at 10° -20° C. Stirring iscontinued for another 30 min., the reaction mixture hydrolyzed byaddition of 300 ml. of water, concentrated under reduced pressure untilthe tetrahydrofuran solvent is substantially removed, and the mixtureextracted with ethyl acetate. The ethyl acetate extract washed withwater, brine, dried over sodium sulfate and concentrated affords aresidual dark brown oil. The residue taken up in benzene and dilutedwith hexane affords 2'-[1-hydroxy-1-(2-pyridyl)ethyl] -p-anisanilide,m.p. 127° -128° C., from aqueous-methanol.

2'-[1-Hydroxy-1-(2-pyridyl)ethyl] -p-anisanilide can alternatively beprepared by reaction of pyridyl lithium witho-(4-methoxybenzamido)-acetophenone according to the procedure ofExample 132 (a).

2'-[1-Hydroxy-1-(2-pyridyl)ethyl] -p-anisanilide (12.0 g., 0.0344 mole)is dehydrated by heating in 150 ml. of 6N hydrochloric acid at steambath temperature for 4 hr. The reaction mixture is poured into ice waterand made basic with concentrated ammonium hydroxide. Extraction of thebasified mixture with ethyl acetate, washing the ethyl acetate extractwith water, brine, and drying over sodium sulfate provides onconcentration 9.9 g. of residual brown oil which is further purified bydissolving in benzene and passing through a column of alumina yielding6.0 g. of 2'-[1-(2-pyridyl)ethylidene] -p-anisanilide.

c. 2'-1-(2-Pyridyl)ethyl-p-anisanilide

2'-[1-(2-Pyridyl)ethylidene] -p-anisanilide (6.0 g., 0.018 mole) isreduced in a Parr apparatus in 100 ml. of acetic acid employing 1.0 g.of 10% palladium on carbon catalyst. The catalyst is collected, thefiltrate concentrated under reduced pressure and the residue thusobtained distributed between water and ethyl acetate. This mixture ismade basic with concentrated ammonium hydroxide and the ethyl acetateextract separated, dried, and concentrated to provide 2'-1-(2-pyridyl)ethyl-p-anisanilide, m.p. 125° -126° C. (corr.), fromaqueous ethanol.

d. 2'-[1-(1-Methyl-2-piperidyl)ethyl]-p-anisanilide 2'-[1-(2-Pyridyl)ethyl]-p-anisanilide alkylated with dimethylsulfate inmethanol solution provides 2-[2-(p-methoxybenzamido)-α-methylbenzyl]-1-methylpyridinium iodide. Reduction of the pyridinium iodide accordingto the procedure of Example 132 (d) provides the diastereoisomers of2'-[1-(1-methyl-2-piperidyl)ethyl]-p-anisanilide. The diastereoisomersare separated into racemic modifications by chromatography employing acolumn of silica gel with ethyl acetate as solvent. Racemate A has amelting point of 151.5°-152° C. (corr.), from aqueous methanol, nmr(CDCl₃) δ 2.00 (s, N-CH₃) and Racemate B has a melting point of 175.5°-179° C. (corr.), from benzene-isopropyl ether, nmr (CDCl.sub. 3) δ 2.10(s, N-CH₃).

Analysis. Calcd. for C₂₂ H₂₈ N₂ O₂ : C, 74.96; H, 8.01; N, 7.95. Found:Racemate A; C, 75.22; H, 8.02; N, 7.68. Racemate B; C, 75.22; H, 7.82;N, 7.91.

EXAMPLE 134 2'-[1-(1-Methyl-2-piperidyl)-2-propyl] -p-anisanilide

a. 2-(p-Bromophenyl)-1-(2-pridyl)propene

2-p-Bromophenyl)- 1-(2-pyridyl-2-propanol is prepared fromp-bromoacetophenone and 2-picoline according to the method of Villani,et al., J. Med. Chem., 13, 359 (1970) in 63% yield. This alcohol (129.1g.) is dehydrated by heating in 1150 ml. of acetic acid-12N hydrochloricacid (3:1) at reflux temperature for 4 hr. The mixture is evaporated invacuo, made basic with concetrated ammonium hydroxide, and extractedwith ethyl acetate. The ethyl acetate extract is washed with water andbrine, dried over sodium sulfate, and evaporated to give a dark brownoil. A solution of the oil in benzene is passed through a columm ofsilica gel. Evaporation of the eluate gave 46.4 g. (26% yield) ofcrystalline 2-(p-bromophenyl)-1-(2-pyridyl)propene, m.p. 71.5°-73.5° C.(corr.).

Analysis. Calcd. for C₁₄ H₁₂ NBr: C, 61.32; H, 4.41; N, 5.11. Found: C,61.04; H, 4.46; N, 4.85.

b. 2-(p-Bromophenyl)-1-(2-pyridyl)propene

A solution of 2-(p-bromophenyl)-1-(2-pyridyl)propene (16.6 g., 0.06mole) in 200 ml. of absolute ethanol containing 0.6 g. of PtO₂ is shakenin a Parr apparatus until one molecular equivalent of hydrogen is takenup. The catalyst is removed by filtration, and the filtrate isevaporated to a semisolid residue which is triturated with hexane. Thehexane soluble portion of this residue is chromatographed on aluminausing benezene to obtain 13.1 g. (81%) of oily2-(p-bromophenyl)-1-(2-pyridyl)-propene. propene. Distillation affordsanalytically pure 2-(p-bromophenyl)-1 -(2-pyridyl)propene, b.p.100°-113° C. (0.2 mm. Hg.), n_(D) ²⁸ 1.5786-1.5820.

Analysis. Calcd. for C₁₄ H₁₄ BrN: C, 60.88; H, 5.11; N, 5.08. Found: C,60.89; H, 5.05; N, 4.88.

c. 2-(4-Bromo-2-nitrophenyl)-1-(2-pyridyl)propane

2-(p-Bromophenyl)-1-(2-pyridyl)propane (11.5 g., 0.043 mole) is heatedin 80 ml. of concentrated nitric acid (specific gravity 1.42, 69-71%)for 4.5 hr. at 80° C. The solution is cooled, quenched in 300 g. of ice,made alkaline with sodium hydroxide, and extracted with ethyl acetate.The extract washed with water and brine, dried over sodium sulfate, andevaporated affords 12.2 g. (88%) of oily nitrated product of sufficientpurity to be used in following "step (d)." Distillation providesanalytically pure 2-(4-bromo-2-nitrophenyl)-1-2-pyridyl)propane, b.p.172° -176° C. (0.2 mm. Hg.), n_(D) ²⁹ 1.5968.

Analysis. Calcd. for C₁₄ H₁₃ N₂ O₂ Br: C, 52.35; H, 4.08; N, 8.73.Found: C, 52.72; H, 4.16; N, 8.44.

d. 2-(o-Anisamido)-1-(2-pyridyl)propane

2-(4-Bromo-2 -nitrophenyl)-1-(2-pyridyl)propane (27.5 g., 0.086 mole) in200 ml. of absolute ethanol containing 9.5 g. of triethylamine and 3.5g. of 10% palladium on carbon is reduced under 3 atmospheres ofhydrogen. The reduced mixture is filtered and the filtrate concentratedaffords an oily residue which is taken up in 200 ml. of pyridine.Anisoyl chloride (16.1 g., 0.094 mole) is added to the pyridine solutionof 2-(2-aminophenyl)-1-(2-pyridyl)propane at 10° -20° C. in 3 minutes.The mixture is stirred overnight at room temperature and evaporated invacuo. The residue is distributed between water and ethyl acetate andmade basic with concentrated ammonium hydroxide. The ethyl acetate layeris separated, washed with water, brine and evaporated to provide 30.4 g.of 2-(o-anisamido)-1-(2-pyridyl)propane. Analytically pure2-(o-anisamido)-1-(2-pyridyl)propane is obtained by chromatographyemploying silica gel and using chloroform as solvent.

Analysis. Calcd. for C₂₂ H₂₂ N₂ O₂ : C, 76.27; H, 6.40; N, 8.09. Found:C, 75.94; H, 6.45; N, 7.86.

e. 2'-[1-(1-Methyl-2-piperidyl)-2-propyl]-p-anisanilide

A mixture of 2-(o-anisamido)-1-(2-pyridyl)propane (11.0 g., 0.32 mole)and dimethyl sulfate (6.0 g., 0.048 mole) is heated at reflux overnightin 200 ml. of methyl alcohol to provide a pyridinium salt. Afterplatinum oxide is added to the methanolic (0.4 g.) solution, the mixtureis reduced under 3 atmospheres until reduction of the pyridinium salt iscomplete. The catalyst is removed by filtration and the filtrateevaporated to afford 2'-[(1-methyl-2-piperidyl)-2-propyl] -p-anisanilideas an oily mixture of diastereoisomers. Partial purification is carriedout by chromatography using silica gel and employing ethyl acetate asthe solvent. A solution of the resultant oil in benzene, diluted withisoproyl ether, provides a white, crystalline solid. Crystallization ofthe white solid from isopropyl acetate-isopropyl ether yields a racemicmodification of 2'-[1-(1-methyl-2-piperidyl)-2-propyl]-p-anisanilidehaving a melting point of 124° -125° C. (corr.), nmr (CDCl.sub. 3), δ2.19 (s, N-CH₃ ).

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₂ : C, 75.37; H, 8.25; N, 7.64. Found:C, 75,42; H, 8.37; N, 7.61.

Evaporation of the mother liquors gives a heavy oil containing,according to nmr, both diastereoisomers of 2'-[1-(1-methyl-2-piperidyl)- 2-propyl]-p-anisanilide in an approximateratio of 30:70, (CDCl.sub. 3), δ 2.19 (s, N-CH₃) and δ 2.23 (s, N-CH₃).

Analysis. Found: C, 75.23; H, 8.18; N, 7.44.

EXAMPLE 135 2'-[1-Hydroxy-3-(1-methyl-2-piperidyl)propyl] -p-anisanilide

A mixture of o-nitrobenzaldehyde (45.3 g., 0.30 mole) triethylorthoformate (48.8 g., 0.33 mole), 75 ml. absolute ethanol, and 10 dropsethanolic HCl is stirred overnight. Potassium carbonate (6.0 g.) isadded to the solution to neutralize the acid, and the reaction mixturefiltered. The filtrate, with 2.0 g. of 10% Pd/C, is shaken on a Parrapparatus, rapidly reducing the nitro group. The catalyst is collected,and Et₃ N (126 ml.) added to the filtrate. The solution is cooled asanisoyl chloride (63.9 g., 0.38 mole) in benzene is added dropwise.After standing overnight, the reaction mixture is concentrated todryness to remove excess Et₃ N and the residue is dissolved in 950 ml.of EtOH and 250 ml. of 1N HCl added. The solution is cooled, providing aprecipitate which is collected yielding 63.8 g. (83%) of solid, m.p.99.5° -100.5° C. Analytically pure o-(4 -methoxy-benzamido)benzaldehydehas a melting point of 99.5° -100.5° C., from ethanol.

Analysis. Calcd. for C₁₅ H₁₃ NO₃ : C, 70.58; H, 5.13; N, 5.49. Found: C,70.28; H, 4.98; N, 5.61.

2-(N-Methyl-2-piperidyl)ethylmagnesium chloride is prepared in 200 ml.of tetrahydrofuran from Mg shavings (5.6 g., 0.230 g.-atom) and2-(2-chloroethyl)-1-methylpiperidine (33.4 g., 0.206 mole). The mixtureis heated at reflux during the addition of the chloride and for a 22 hr.period after the addition. After cooling to room temperature, a solutionof o-(4-methoxybenzamido)benzaldehyde (17.5 g., 0.069 mole) in 235 ml.tetrahydrofuran is added dropwise. The mixture is heated at reflux for 3hr., cooled and hydrolyzed with 27 ml. of saturated aqueous NH₄ Cl. Thesolution is filtered and evaporated to give a residue which is dissolvedin 125 ml. of CH₃ CN. The first crop obtained on cooling is collected,12.8 g., m.p. 131° -136° C., and recrystallized five times from CH₃ CN,yielding 4.1 g. of 2'-[1-hydroxy-3-(1-methyl-2-piperidyl)propyl]-p-anisanilide (Racemate B), m.p. 148.0° -149° C.(corr.)

Further cooling of the mother liquor from the first crop affords 6.1 g.of additional product, m.p. 119°-125° C. Crystallization from CH₃ CHyields 1.8 g. of 4-methoxy-2'-[1-hydroxy-3-(1-methyl-2-piperidyl)propyl]benzanilide (Racemate A), m.p. 129.5° -130.5° C.(corr.).

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₃ : C, 72.22; H, 7.91; N, 7.32. Found:(Racemate A); C, 72.39; H, 7.92; N, 7.25; (Racemate B); C, 72.10; H,7.69; N, 7.36.

EXAMPLE 136 4-Methoxy-2'-[3-(1-methyl-2-piperidyl)propyl] -benzanilide

A mixture of 5% Pd/BaSO₄ and AcOH (100 ml.) is shaken on a Parrhydrogenator for 0.5 hr. prior to adding a solution of 4-methoxy-2'-[1-hydroxy-3-(1-methyl-2-piperidyl)propyl]benzanilide (8.0 g., 0.021mole), AcOH (150 ml) and 70% HClO.sub. 4 (8.0 ml, 0.09 mole). Thehydrogenation is complete in about 3 hr. The catalyst is filtered offand 50% NaOH (5 ml.) added to the filtrate to neutralize the HClO.sub.4. After concentration, dilution with H₂ O and basification with 50%NaOH, the mixture is extracted with EtOAc. The EtOAc extract is washedwith water, dried over magnesium sulfate and concentrated to give anoil, 8.3 g., which is crystallized from 75 ml. of EtOAc. The product,m.p. 107° -110° C., is filtered off and recrystallized from EtOAc,providing 4.2 g. (55%) of 4-methoxy-2'-[3(1-methyl-2-piperidyl)propyl]benzanilide, m.p. 108.5° -110° C.

Analysis. Calcd. for C₂₃ H₃₀ N₂ O₂ : C, 75.37; H, 8.25; N, 7.64. Found:C, 75.58; H, 8.24; N, 7.55.

EXAMPLE 137 2'-(2-piperidylmethyl)-p-anisanilide

Reduction of 2'-(2-pyridylmethyl)-p-anisanilide (4.65 g., 0.0146 mole)according to the procedure of Walker, J. Org. Chem., 27, 2966 (1962), in150 ml. of acetic acid with 2.35 g. of 10% palladium on carbon catalystaffords 2'-(2-piperidylmethyl-p-anisanilide, m.p. 108° -109° C. (corr.),from benzene-hexane.

Analysis. Calcd. for C₂₀ H₂₄ N₂ O₂ : C, 74.04; H, 7.46; N, 8.64. Found:C, 74.33; H, 7.27; N, 8.73.

EXAMPLE 138 2' -[Hydroxy(2-piperidyl)methyl]-p-anisanilide

Reduction of 2' -[hydroxy(2-pyridyl)methyl]-p-anisanilide, according tothe procedure of Example 137 provides 2' -[hydroxy(2-piperidyl)methyl]-p-anisanilide, m.p. 157.5° -159.5° C. (corr.), from benzene.

Analysis. Calcd. for C₂₀ H₂₄ N₂ O₃ : C, 70.56; H, 7.11; N, 8.23. Found:C, 70.60; H, 7.12; N, 8.04.

EXAMPLE 139 2'-[2-(2-Piperidyl)ethyl]-p-anisanilide hemimucate

Hydrogenation of 20'-[2-(2-pyridyl)ethyl]-p-anisanilide according to theprocedure of Example 117 affords 2'-[2-(2-piperidyl)-ethyl]-p-anisanilide hemimucate, m.p. 169° -169.5° C., from water and thenisopropyl ether.

Analysis. Calcd. for C₂₁ H₂₆ N₂ O₂. 1/2C₆ H₁₀ O₈ : C, 64.98; H, 7.05; N,6.32. Found: C, 64.81; H, 7.22, N, 6.06.

EXAMPLE 140 2-[2-[(p-Methoxybenzyl)amino]phenethyl]-1 -methylpiperidinehemimucate

A solution of 4-methoxy-2'-[2(1-methyl- 2-piperidyl)ethyl]benzanilide(10 g., 0.028 mole) in 100 ml. of tetrahydrofuran is added to 150 ml. of1 molar borane:THE complex. After stirring 1 hr. and heating underreflux 1 hr., 6N HCl (50 ml.) is added dropwise to the reaction mixture.The reaction mixture is evaporated and the residue dissolved in 200 ml.of water. Basification of the solution followed by ether extraction andevaporation of the dried (MgSO₄) ethereal extracts affords an oil whichis distilled, b.p. 220° C., 0.05 Torr, and then converted to the mucatesalt by treating with mucic acid in ethanol. Crystallization from wateryields 5.0 g. (40%), of analytically pure 2-[2-[(p-methoxybenzyl)amino]phenethyl]-1 -methylpiperidine hemimucate, m.p.164.5° -165.5° C. (dec.)(corr.).

Analysis: Calcd. for C₂₂ H₃₀ N₂ O.1/2C₆ H₁₀ O₈ : C, 67.68; H, 7.96; N,6.32. Found: C, 67.60; H, 7.80; N, 6.32.

EXAMPLE 141 Optically active 2'-[2-(1-methyl-2-piperidyl)-ethyl]cinnamanilide

a. Resolution of 2-(o-aminophenethyl)-1-methylpiperidine

Fractional crystallization of the d-camphoric acid salt of racemic2-(o-aminophenethyl)-1-methylpiperidine from 95% EtOH provides afraction with the following properties: m.p. 112° -132° C. [α]_(D)²⁵.sup.° = -4.0° (1% in 95% EtOH). This fraction is converted to thefree base, distilled, and the portion boiling at 105° -106° C. (0.02Torr), n_(D) ³⁰.sup.° 1.5546 collected (stereoisomer A). Adihydrochloride of 2-(o-aminophenethyl)- 1-methylpiperidine stereoisomerA has the following properties: m.p. 240° -250° C.; [α]_(D) ²⁵.sup.° =-12.9° (1% in 95% EtOH).

Analysis. Calcd. for C₁₄ H₂₂ N₂. 2HCl: C, 57.73; H, 8.31; N, 9.62.Found: C, 57.77; H, 8.51; N, 9.58.

The ethanolic mother liquors, enriched in the d-camphoric acid salt ofstereoisomer B from the isolation of 2-(o-aminophenethyl)-1-methylpiperidine (stereoisomer A), are evaporated and the residueconverted to the free base. The base is converted to the l-camphoricacid salt which is fractionally crystallized from 95% EtOH. Twofractions are obtained having a rotation of [α]_(D) ²⁵.sup.° = + 4.1°(1% in 95% EtOH) and [α]_(D) ²⁵.sup.° = + 4.4° (1% in 95% EtOH). Thesefractions combined, converted to the free base and chromatographed(alumina, EtOAc) to remove a small amount of a polar impurity, provide2-(o-aminophenethyl)-1-methyl piperidine (stereoisomer B).

b. l-2'-[2-(1-Methyl-2piperidyl)ethyl]cinnamanilide

Reaction of 2-(o-aminophenethyl)1-methylpiperidine (stereoisomer A) andcinnamoyl chloride according to the procedure of Example 25 affordsl-2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, m.p. 129° -130° C.(corr.) from ethyl acetate: [α]_(D) ²⁷.sup.° = -42.8° (2% in 95% EtOH).

Analysis. Calcd. for C₂₃ H₂₈ N₂ O: C, 79.27; H, 8.10; N, 8.04. Found: C,79.09; H, 8.14; N, 7.95.

c. d-2'-[2(1-Methyl-2-piperidyl)ethyl]cinnamanilide

Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (stereoisomer B) andcinnamoyl chloride according to the procedure of Example 25 affordsd-2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, m.p. 128.5° -129.5°C. (corr.) from heptane and then isopropanol) [α]_(D) ²⁶.sup.° = + 42.9°(2% in 95% EtOH).

Analysis. Found: C, 79.46; H, 8.12; N, 7.92.

EXAMPLE 142 Optically active 4-methoxy-2'-[2(1-methyl-2-piperidyl)ethyl]benzanilide

a. l-4-Methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide

Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (stereoisomer A) andanisoyl chloride according to the procedure of Example 25 affordsl-4-methoxy-2'-[2-(1methyl-2-piperidyl)ethyl]benzanilide, m.p. 126.5°-127.5° C. (corr.), from heptane; [α]_(D) ²⁹.sup.° = - 39.3° (2% in 95%EtOH).

Analysis. Calcd. for C₂₂ H₂₈ N₂ O₂ : C, 74.96; H, 8.01; N, 7.95 Found:C, 74.97; H, 8.07; N, 7.79.

b. d-4-Methoxy-2'-[2-(1-methyl-2-piperidyl)ethylbenzanilide

Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (stereoisomer B) andanisoyl chloride according to the procedure of Example 25 affords d-4-methoxy-2'-[2-(1 -methyl-2-piperidyl)ethyl]benzanilide, m.p. 127°-127.5° C. (corr.), from heptane; [α]_(D) ²⁵.sup.° = + 41.5° (2% in 95%EtOH).

Analysis. Found: C, 75.02; H, 7.76; N, 7.83.

While several specific embodiments are disclosed in the foregoingspecification, it will be appreciated that other modifications may bemade without departing from the spirit and scope of the appended claims.

What is claimed:
 1. A compound selected from the group consisting ofsubstituted piperidines having Formula I ##STR45## wherein R¹ representshydrogen;R² represents hydrogen or methylenedioxy attached in thebenzenoid 4,5-position; R³ represents hydrogen or methyl; R⁴ representshydrogen; R⁵ is selected from the group consisting of lower alkanoyl offrom 1 to 4 carbon atoms inclusive, lower alkanesulfonyl of from 1 to 4carbon atoms inclusive, ##STR46## and a pharmaceutically acceptable saltthereof.
 2. The compound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl] -2-thiophenecarboxanilide.
 3. Thecompound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]-2-thiophenecarboxanilide mucate. 4.The compound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]-2-thiophenecarboxanilidehydrochloride.
 5. The compound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide.
 6. The compound of thegroup defined in claim 1 which is2'-[2-(1-methyl-2piperidyl)ethyl]formanilide hydrochloride.
 7. Thecompound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide.
 8. The compound of thegroup defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide mucate.
 9. The compound ofthe group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide hydrochloride.
 10. Thecompound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]methanesulfonanilide.
 11. The compoundof the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]methanesulfonanilide hydrochloride.12. The compound of the group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]picolinanilide.
 13. The compound ofthe group defined in claim 1 which is2'-[2-(1-methyl-2-piperidyl)ethyl]phenylpropiolanilide.
 14. A compoundselected from the group consisting of o-aminophenethylpiperidines havingthe formula ##STR47## and acid addition salts thereof wherein R¹represents hydrogen, lower alkyl of from 1 to 4 carbon atomsinclusive;R² represents hydrogen or lower alkoxy of from 1 to 4 carbonatoms inclusive; R³ represents a lower alkyl of from 1 to 4 carbon atomsinclusive; and R⁴ represents hydrogen, lower alkyl of from 1 to 4 carbonatoms inclusive, or a dialkyl carboxamido wherein the dialkyl groupshave from 1 to 4 atoms inclusive.
 15. The compound of the group definedin claim 14 which is 2-(o-aminophenethyl)-1-methylpiperidine.
 16. Thecompound of the group defined in claim 14 which is2-(o-aminophenethyl)-1-methylpiperidine dihydrochloride.
 17. Thecompound 2-[2-[(p-methoxybenzyl)amino]phenethyl]-1-methylpiperidinehemimucate.